Compositions and methods for treating cardiovascular diseases

ABSTRACT

The present specification discloses pharmaceutical compositions, methods of preparing such pharmaceutical compositions, and methods and uses of treating a cardiovascular disease in an individual using such pharmaceutical compositions.

This continuation application claims priority pursuant to 35 U.S.C. §120 to U.S. patent application Ser. No. 15/219,245, filed Jul. 25, 2016,a continuation that claims priority to U.S. patent application Ser. No.14/520,159, filed Oct. 21, 2014, now U.S. Pat. No. 9,427,422, acontinuation that claims priority to U.S. patent application Ser. No.13/365,828, filed Feb. 3, 2012, now U.S. Pat. No. 8,895,537, acontinuation-in-part application that claims priority to patentapplication PCT/GB2011/052115, filed Oct. 31, 2011, an internationalpatent application that claims priority to GB 1018289.7, filed Oct. 29,2010, and claims priority to GB 1113730.4, filed Aug. 10, 2011, GB1113729.6, filed Aug. 10, 2011, GB 1113728.8, filed Aug. 10, 2011, andGB 1101937.9, filed Feb. 4, 2011, each of which is hereby incorporatedby reference in its entirety.

Lipids constitute a broad group of naturally occurring hydrophobic oramphiphilic molecules that include fatty acids, glycerolipids,glycerophospholipids, sphingolipids, saccharolipids, and polyketides,sterol lipids and prenol lipids. The main biological functions of lipidsinclude energy storage, as structural components of cell membranes, andas important signaling molecules. Given these fundamental roles, allcells use and rely on lipids. One process used to transport lipids tocells involves apolipoproteins. Apolipoproteins are proteins that bindto lipids to form lipoproteins, which are the vehicles used fortransporting the lipids, including triglycerides and cholesterol,through the lymphatic and circulatory systems. The lipid components oflipoproteins are not themselves soluble in water. However, because oftheir amphipathic properties, apolipoproteins and other amphipathicmolecules (such as, e.g., phospholipids) can surround the lipids,creating the lipoprotein particle that is itself water-soluble, and canthus be carried through water-based circulation, i.e. blood and lymph,etc.

There five major groups of lipoprotein particles, and the lipoproteindensity and type of apolipoproteins it contains determines the fate ofthe particle and its influence on metabolism. Chylomicrons are thelargest lipoprotein particle and these particles carry triglyceridesfrom the intestines to the liver, skeletal muscle, and adipose tissue.Very low-density lipoprotein (VLDL) particles are large,triglyceride-rich lipoprotein secreted by the liver that transportstriglycerides to adipose tissue and muscle. The third group lipoproteinparticles are intermediate-density lipoprotein (IDL) particles, anintermediate between VLDL and low-density lipoprotein (LDL). IDLparticles are formed when lipoprotein lipase removes triglycerides fromVLDL particles in the capillaries and the return these smaller particlesto the circulation. The IDL particles have lost most of theirtriglyceride, but they retain cholesteryl esters. Some of the IDLparticles are rapidly taken up by the liver; others remain incirculation, where they undergo further triglyceride hydrolysis and areconverted to LDL. LDL particles carry cholesterol from the liver tocells of the body, where these particles bind to LDL receptors that aresubsequently endocytosed in vesicles form via clathrin-coated pits.After the clathrin coat is shed, the vesicles ultimately deliver the LDLto lysosomes where the cholesterol esters are hydrolyzed. The last groupof lipoprotein particles is high-density lipoprotein (HDL) particles,which collect cholesterol from the body's tissues and bring it back tothe liver.

High levels of lipids, e.g., cholesterol, and/or lipoprotein particles,e.g., VLDL, IDL, and/or LDL can have deleterious effects on thecardiovascular system. For example, as a major extracellular carrier ofcholesterol, LDL plays important physiologic roles in cellular functionand regulation of metabolic pathways. Cells have complex feedbackmechanisms that ensure sufficient supply of cholesterol and prevent itsexcessive accumulation in the blood. However, under pathologicconditions of, e.g., hyperlipidemia, oxidative stress and/or geneticdisorders, specific components of LDL become oxidized or otherwisemodified, with a consequence that cholesterol transport by such modifiedLDL is diverted from its physiologic targets and accumulates in theblood.

One effect of this accumulation is the high amounts of cholesteroland/or LDL become embedded in the walls of blood vessels, an in so doinginvokes an inflammatory response. In response to this inflammation,blood monocytes adhere to the endothelium, transmigrate into thesubendothelial space, and differentiate toward macrophages. Macrophages,in turn, engulf the cholesterol deposits and modified LDL byphagoocytosis via scavenger receptors, which are distinct from LDLreceptors. However, the adaptive mechanisms mediated by macrophages arenot sufficient to process the uncontrolled cholesterol and/or LDLdeposition seen under pathologic conditions. As a result, thelipid-laden macrophages transform into “foam cells” or “foamy cells”having a M1 phenotype. Both cholesterol/LDL deposition and the attendantfoam cell-mediated pro-inflammatory reactions in the blood wall lead tothe development of atherosclerotic lesions. Left untreated, this lipidaccumulation and pro-inflammatory response result in the progression ofthe lesions, which eventually leads to a cardiovascular disease.

Another effect of high cholesterol/LDL accumulation in the blood is theformation LDL aggregates or LDL agglomerates. Being of high molecularweight, LDL agglomerates initiate an inflammatory response in a mannersimilar to that invoked by pathogens like viruses or bacteria. Theinflammatory response triggers agglomerate uptake by macrophages whichconverts these cells into foam cells having a M1 phenotype, and therelease of inflammation inducing molecules. Once again, left untreated,the lipid accumulation and pro-inflammatory response can result in acardiovascular disease.

Attempts to treat cardiovascular disease by controlling levels of lipidsand/or lipoproteins in the blood have met with limited success. Forexample, although administration of statins reduces cardiovascular riskin some individuals, these therapeutic compounds do not reducetriglyceride levels. Thus, in individuals at cardiovascular risk whoexhibit deleteriously high levels of triglycerides, another class oftherapeutic compounds called fibrates may be administered. However,although lowering triglyceride and LDL levels, fibrates do not affectthe level of HDL, the lipoprotein particle known to be protectiveagainst cardiovascular disease. Lastly, combination treatments involvingstatins and fibrates, while effective, cause a significant increase tothe risk of myopathy and rhabdomyolysis, and therefore can only becarried out under very close medical supervision. In view of theseproblems, there is, therefore, clearly a need for improved compounds andcompositions for the use and treatment of cardiovascular diseases,including those associated with high lipid and/or lipoprotein levels.

The present specification discloses pharmaceutical compositions andmethods for treating an individual suffering from a cardiovasculardisease. The pharmaceutical compositions disclosed herein areessentially a lipid delivery system that enables a therapeutic compoundhaving an activity that modulates lipid and/or lipoprotein levels to bedelivered in a manner that more effectively treats a cardiovasculardisease.

SUMMARY

Aspects of the present specification disclose a pharmaceuticalcomposition comprising a therapeutic compound and apharmaceutically-acceptable adjuvant. A therapeutic compound may have anactivity that normalizes lipid levels. Other aspects of the presentspecification disclose a pharmaceutical composition comprising atherapeutic compound disclosed herein, a pharmaceutically-acceptablesolvent, and a pharmaceutically-acceptable adjuvant. In other aspects,the pharmaceutical compositions disclosed herein further comprise apharmaceutically-acceptable stabilizing agent.

Other aspects of the present specification disclose a method ofpreparing a pharmaceutical composition, the method comprising the stepof contacting a therapeutic compound with a pharmaceutically-acceptableadjuvant under conditions which allow the formation of thepharmaceutical composition. Other aspects of the present specificationdisclose a method of preparing a pharmaceutical composition, the methodcomprising the steps: a) contacting a pharmaceutically-acceptablesolvent with a therapeutic compound under conditions which allow thetherapeutic compound to dissolve in the pharmaceutically-acceptablesolvent, thereby forming a solution, wherein the therapeutic compoundhas an activity that normalizes lipid levels, and b) contacting thesolution formed in step (a) with a pharmaceutically-acceptable adjuvantunder conditions which allow the formation of the pharmaceuticalcomposition. In other aspects, the method of preparing disclosed hereinfurther comprises c) removing the pharmaceutically-acceptable solventfrom the pharmaceutical composition.

Other aspects of the present specification disclose a pharmaceuticalcomposition, the pharmaceutical composition made according to a methodcomprising the step of contacting a therapeutic compound with apharmaceutically-acceptable adjuvant under conditions which allow theformation of the pharmaceutical composition. Other aspects of thepresent specification disclose a pharmaceutical composition, thepharmaceutical composition made according to a method comprising thesteps: a) contacting a pharmaceutically-acceptable solvent with atherapeutic compound under conditions which allow the therapeuticcompound to dissolve in the pharmaceutically-acceptable solvent, therebyforming a solution, wherein the therapeutic compound has an activitythat normalizes lipid levels, and b) contacting the solution formed instep (a) with a pharmaceutically-acceptable adjuvant under conditionswhich allow the formation of the pharmaceutical composition. In otheraspects, the method of making a pharmaceutical composition disclosedherein further comprises c) removing the pharmaceutically-acceptablesolvent from the pharmaceutical composition.

Other aspects of the present specification disclose a method of treatingan individual with a cardiovascular disease, the method comprising thestep of administering to the individual in need thereof a pharmaceuticalcomposition disclosed herein, wherein administration results in areduction in a symptom associated with the cardiovascular disease,thereby treating the individual.

Other aspects of the present specification disclose a use of apharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of a cardiovascular disease.

Other aspects of the present specification disclose a use of apharmaceutical composition disclosed herein for the treatment of acardiovascular disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effects of a pharmaceutical composition disclosedherein on survival against Influenza A/PR/8/34 lethal challenge.Ibuprofen 335 μg=Group A; Ctrol ORAL=Group B; and ibuprofen 335 μg o/eORAL (BC1054)=Group C.

FIGS. 2A-B show the effects of a pharmaceutical composition disclosedherein on in vivo levels of Th2 cytokines in the lungs of survivingmice. FIG. 2A shows a graph of the effects of a pharmaceuticalcomposition disclosed herein on in vivo levels of IL-10, whereas FIG. 2Bshows a graph of the effects of a pharmaceutical composition disclosedherein on in vivo levels of IL-4. BC1054 ORAL=Group A; VehicleORAL=Group B; and BC1054 Lipid ORAL=Group C.

FIGS. 3A-C show the effects of a pharmaceutical composition disclosedherein on in vivo levels of Th2 cytokines in the lungs of survivingmice. FIG. 3A shows a graph of the effects of a pharmaceuticalcomposition disclosed herein on in vivo levels of IL-10; FIG. 3B shows agraph of the effects of a pharmaceutical composition disclosed herein onin vivo levels of TNF-α; and FIG. 3C shows a graph of the effects of apharmaceutical composition disclosed herein on in vivo levels of IFN-γ.BC1054 ORAL=Group A; Vehicle ORAL=Group B; and BC1054 Lipid ORAL=GroupC.

DESCRIPTION

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. As used herein, the term “pharmaceutically acceptable”means any molecular entity or composition that does not produce anadverse, allergic or other untoward or unwanted reaction whenadministered to an individual. As used herein, the term“pharmaceutically acceptable composition” is synonymous with“pharmaceutical composition” and means a therapeutically effectiveconcentration of an active ingredient, such as, e.g., any of thetherapeutic compounds disclosed herein. A pharmaceutical compositiondisclosed herein is useful for medical and veterinary applications. Apharmaceutical composition may be administered to an individual alone,or in combination with other supplementary active ingredients, agents,drugs or hormones.

A pharmaceutical composition disclosed herein may optionally include apharmaceutically-acceptable carrier that facilitates processing of anactive ingredient into pharmaceutically-acceptable compositions. As usedherein, the term “pharmacologically-acceptable carrier” is synonymouswith “pharmacological carrier” and means any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary or excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active ingredients can besoluble or can be delivered as a suspension in the desired carrier ordiluent. Any of a variety of pharmaceutically acceptable carriers can beused including, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like;solvents; dispersion media; coatings; antibacterial and antifungalagents; isotonic and absorption delaying agents; or any other inactiveingredient. Selection of a pharmacologically acceptable carrier candepend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activeingredient, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins,20th ed. 2000); Goodman & Gilman's The Pharmacological Basis ofTherapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4th edition 2003). These protocols areroutine procedures and any modifications are well within the scope ofone skilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, sweetening orflavoring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, citratebuffers, phosphate buffers, neutral buffered saline, phosphate bufferedsaline and borate buffers. It is understood that acids or bases can beused to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition and chelants, such as, e.g., DTPA orDTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustorsuseful in a pharmaceutical composition include, without limitation,salts such as, e.g., sodium chloride, potassium chloride, mannitol orglycerin and other pharmaceutically acceptable tonicity adjustor. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

In one embodiment, a pharmaceutical composition disclosed hereincomprises a therapeutic compound having an activity that normalizeslipid levels and a pharmaceutically-acceptable adjuvant. In anotherembodiment, a pharmaceutical composition disclosed herein comprises atherapeutic compound having an activity that normalizes lipid levels, apharmaceutically-acceptable solvent, and a pharmaceutically-acceptableadjuvant. In aspects of this embodiment, a pharmaceutical compositiondisclosed herein may further comprise a pharmaceutically-acceptablestabilizing agent. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may further comprise apharmaceutically-acceptable carrier, a pharmaceutically-acceptablecomponent, or both pharmaceutically-acceptable carrier andpharmaceutically-acceptable component.

Aspects of the present specification disclose, in part, a therapeuticcompound. A therapeutic compound is a compound that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. A therapeuticcompound disclosed herein may be used in the form of a pharmaceuticallyacceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride.Additionally, therapeutic compound disclosed herein may be provided asracemates, or as individual enantiomers, including the R- orS-enantiomer. Thus, the therapeutic compound disclosed herein maycomprise a R-enantiomer only, a S-enantiomer only, or a combination ofboth a R-enantiomer and a S-enantiomer of a therapeutic compound. Atherapeutic compound disclosed herein may have an activity thatnormalizes lipid levels. As used herein, the term “normalizes lipidlevels” refers to an activity that reduces a level of a lipid orlipoprotein that is deleteriously high to a normal or non-harmful level,increases a level of a lipid or lipoprotein to a level that isbeneficial to an individual, or both. For example, a therapeuticcompound having an activity that normalizes lipid levels may reducecholesterol and/or LDL that is deleteriously high to a normal ornon-harmful level, increase HDL to a level that is beneficial to anindividual, or both.

Lipid and lipoprotein abnormalities are common in the generalpopulation, and are regarded as a modifiable risk factor forcardiovascular disease due to their influence on atherosclerosis.Because studies have shown that higher levels of LDL particles promotehealth problems and cardiovascular disease, they are often informallycalled the “bad cholesterol” particles. This is in contrast to HDLparticles, which are frequently referred to as “good cholesterol” or“healthy cholesterol” particles, because higher HDL levels arecorrelated with cardiovascular health. High levels of HDL are thought toreduce LDL levels by acting as a sink for excess triglycerides levels inLDL.

In an embodiment, a therapeutic compound disclosed herein has ananti-hyperlipidemia activity. In an aspect of this embodiment, atherapeutic compound disclosed herein has anti-hyperlipidemia activitycapable of reducing the levels of VLDL, IDL, LDL, or a combinationthereof. In other aspects of this embodiment, a therapeutic compounddisclosed herein has anti-hyperlipidemia activity capable of reducingthe levels of VLDL, IDL, LDL, or a combination thereof by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In yet other aspects of thisembodiment, a therapeutic compound disclosed herein hasanti-hyperlipidemia activity capable of reducing the levels of VLDL,IDL, LDL, or a combination thereof in a range from, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein increasesthe level of HDL. In an aspect of this embodiment, a therapeuticcompound disclosed herein increases the level of HDL by, e.g., at least2%, at least 3%, at least 10%, at least 12%, at least 15%, at least 17%,at least 20%, at least 22%, at least 25%, at least 27%, at least 30%, atleast 32%, at least 35%, at least 37%, at least 40%, at least 42%, atleast 45% or at least 47%. In yet other aspects of this embodiment, atherapeutic compound disclosed herein increases the level of HDL in arange from, e.g., about 2% to about 100%, about 10% to about 50%, about15% to about 50%, about 20% to about 50%, about 25% to about 50%, about30% to about 50%, about 35% to about 50%, about 40% to about 50%, about2% to about 45%, about 10% to about 45%, about 15% to about 45%, about20% to about 45%, about 25% to about 45%, about 30% to about 45%, about35% to about 45%, about 2% to about 40%, about 10% to about 40%, about15% to about 40%, about 20% to about 40%, about 25% to about 40%, orabout 30% to about 40%, about 2% to about 35%, about 10% to about 35%,about 15% to about 35%, about 20% to about 35%, or about 25% to about35%.

When cholesterol and/or lipoproteins like LDL become embedded in thewalls of blood vessels, an immune response can be invoked thatsubsequently results in a chronic inflammatory response. Such chronicinflammation can that eventually can weaken and damage the bloodvessels, causing them to burst. Thus, one consequence of modulating thelevels of a lipid or lipoprotein is the reduction or elimination of achronic inflammation. Prostaglandins mediate a local inflammatoryresponse and are involved in all inflammatory functions through actionon prostaglandin receptors and mediate inflammatory signaling includingchemotaxis (macrophages, neutrophils and eosinophils), vasodilation andalgesia. However, the PG-mediated inflammatory response is self-limiting(resolving). The principle resolution factor is a prostaglandin called15dPGJ2, which is an endogenous agonist of peroxidaseproliferator-activator receptor gamma (PPAR-γ) signaling. PPARγsignaling pathway 1) induces apoptosis of Macrophage M1 cells, therebyreducing the levels of Th1 pro-inflammatory cytokines and 2) promotesdifferentiation of monocytes into Macrophage M2 cells. Macrophage M2cells produce and release Th2 anti-inflammatory cytokines.

In an embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of aninflammation inducing prostaglandin. In other aspects of thisembodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of ainflammation inducing prostaglandin released from a sensory neuron by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In yet other aspects ofthis embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of ainflammation inducing prostaglandin released from a sensory neuron in arange from, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity substantially similar to 15dPGJ2. In aspectsof this embodiment, a therapeutic compound disclosed herein ananti-inflammatory activity that is, e.g., at least 5%, at least 15%, atleast 25%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90% or atleast 95% of the activity observed for 15dPGJ2. In other aspects of thisembodiment, a therapeutic compound disclosed herein an anti-inflammatoryactivity that is in a range from, e.g., about 5% to about 100%, about50% to about 100%, about 60% to about 100%, about 70% to about 100%,about 80% to about 100%, about 25% to about 90%, about 50% to about 90%,about 60% to about 90%, about 70% to about 90%, about 80% to about 90%,about 25% to about 80%, about 50% to about 80%, about 60% to about 80%,about 70% to about 80%, about 25% to about 70%, about 50% to about 70%,about 25% to about 60%, about 50% to about 60%, or about 25% to about50% of the activity observed for 15dPGJ2.

The peroxisome proliferator-activated receptors (PPARs) are a group ofnuclear receptor proteins that function as transcription factorsregulating the expression of genes. All PPARs are known toheterodimerize with the retinoid X receptor (RXR) and bind to specificregions on the DNA of target genes called peroxisome proliferatorhormone response elements (PPREs). PPARs play essential roles in theregulation of cellular differentiation, development, and metabolism(carbohydrate, lipid, protein), and tumorigenesis of higher organisms.The family comprises three members, PPAR-α, PPAR-γ, and PPAR-δ (alsoknown as PPAR-β). PPAR-α is expressed in liver, kidney, heart, muscle,adipose tissue, as well as other tissues. PPAR-δ is expressed in manytissues but markedly in brain, adipose tissue, and skin. PPAR-γcomprises three alternatively-spliced forms, each with a differentexpression pattern. PPAR-γ1 is expressed in virtually all tissues,including heart, muscle, colon, kidney, pancreas, and spleen. PPAR-γ2 isexpressed mainly in adipose tissue. PPAR-γ3 is expressed in macrophages,large intestine, and white adipose tissue. Endogenous ligands for thePPARs include free fatty acids and eicosanoids. PPAR-γ is activated byPGJ2 (a prostaglandin), whereas PPAR-α is activated by leukotriene B4.

The de novo production of HDL particles by the liver is thought to betriggered by activation of the PPAR signaling pathways. So PPAR agoniststhat are targeted to cell types involved in lipid processing(macrophage, adipocytes and hepatocytes) through the normal lipidabsorption mechanism will selectively increase beneficial HDL levels andso normalize blood lipid profiles and treat a cardiovascular disease.

In an embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating all PPAR signalingpathways. Such a therapeutic compound includes a PPAR pan-agonist. Inother embodiments, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating one or two of the PPARsignaling pathways. Such a therapeutic compound includes a selectivePPAR agonist.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating a PPAR-α signalingpathway. In aspects of this embodiment, a therapeutic compound disclosedherein stimulates a PPAR-α signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. In other aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPAR-α signalingpathway in a range from, e.g., about 5% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 25% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 80% to about 90%, about 25%to about 80%, about 50% to about 80%, about 60% to about 80%, about 70%to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%to about 60%, about 50% to about 60%, or about 25% to about 50%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating a PPAR-δ signalingpathway. In aspects of this embodiment, a therapeutic compound disclosedherein stimulates a PPAR-δ signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. In other aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPAR-δ signalingpathway in a range from, e.g., about 5% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 25% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 80% to about 90%, about 25%to about 80%, about 50% to about 80%, about 60% to about 80%, about 70%to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%to about 60%, about 50% to about 60%, or about 25% to about 50%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating a PPARγ signalingpathway. A therapeutic compounds disclosed herein may be capable ofbinding to all isoforms of PPAR-γ, or may be capable of selectivelybinding to either PPAR-γ1, PPAR-γ2, PPAR-γ3, or any combination of twothereof. In aspects of this embodiment, a therapeutic compound disclosedherein stimulates a PPARγ signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. In other aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPARγ signalingpathway in a range from, e.g., about 5% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 25% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 80% to about 90%, about 25%to about 80%, about 50% to about 80%, about 60% to about 80%, about 70%to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%to about 60%, about 50% to about 60%, or about 25% to about 50%.

Macrophages are activated and polarized into distinct phenotypesexpressing unique cell surface molecules and secreting discrete sets ofcytokines and chemokines. The classical M1 phenotype supportspro-inflammatory Th1 responses driven by cytokines such as, e.g.,Interleukin-6 (IL-6), IL-12 and IL-23, while the alternate M2 phenotypeis generally supportive of anti-inflammatory processes driven by IL-10.M2 cells can be further classified into subsets, M2a, M2b, and M2c,based on the type of stimulation and the subsequent expression ofsurface molecules and cytokines.

In yet another embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of promoting the resolvingphenotypic change of M1 to M2. In an aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of inducing apoptosis of Macrophage M1 cells. In another aspectof this embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of promoting differentiation ofMacrophage M2 cells. In yet another aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of inducing apoptosis of Macrophage M1 cells and promotingdifferentiation of Macrophage M2 cells.

In still another embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of modulating Th1 and Th2cytokines. In an aspect of this embodiment, a therapeutic compounddisclosed herein has an anti-inflammatory activity capable of reducingthe levels of Interferon-gamma (IFNγ), Tumor necrosis factor-alpha(TNF-α), IL-12, or a combination thereof released from a Th1 cell. Inother aspects of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof IFNγ, TNF-α, IL-12, or a combination thereof released from a Th1 cellby, e.g., at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, or at least 90%. Inyet other aspects of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof IFNγ, TNF-α, IL-12, or a combination thereof released from a Th1 cellin a range from, e.g., about 5% to about 100%, about 10% to about 100%,about 20% to about 100%, about 30% to about 100%, about 40% to about100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 100%, about 80% to about 100%, about 10% to about 90%, about 20%to about 90%, about 30% to about 90%, about 40% to about 90%, about 50%to about 90%, about 60% to about 90%, about 70% to about 90%, about 10%to about 80%, about 20% to about 80%, about 30% to about 80%, about 40%to about 80%, about 50% to about 80%, or about 60% to about 80%, about10% to about 70%, about 20% to about 70%, about 30% to about 70%, about40% to about 70%, or about 50% to about 70%.

In another aspect of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of increasing thelevels of IL-10 released from a Th2 cell. In other aspects of thisembodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of increasing the levels of IL-10released from a Th2 cell by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In yet other aspects of this embodiment, a therapeutic compounddisclosed herein has an anti-inflammatory activity capable of increasingthe levels of IL-10 released from a Th2 cell in a range from, e.g.,about 5% to about 100%, about 10% to about 100%, about 20% to about100%, about 30% to about 100%, about 40% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 10% to about 90%, about 20% to about 90%, about 30%to about 90%, about 40% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 10% to about 80%, about 20%to about 80%, about 30% to about 80%, about 40% to about 80%, about 50%to about 80%, or about 60% to about 80%, about 10% to about 70%, about20% to about 70%, about 30% to about 70%, about 40% to about 70%, orabout 50% to about 70%.

In another aspect of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof IFNγ, TNF-α, IL-12, or a combination thereof released from a Th1 celland increasing the levels of IL-10 released from a Th2 cell. In otheraspects of this embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of reducing the levels of IFNγ,TNF-α, IL-12, or a combination thereof released from a Th1 cell by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%, and capable ofincreasing the levels of IL-10 released from a Th2 cell by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In yet other aspects of thisembodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of IFNγ,TNF-α, IL-12, or a combination thereof released from a Th1 cell in arange from, e.g., about 5% to about 100%, about 10% to about 100%, about20% to about 100%, about 30% to about 100%, about 40% to about 100%,about 50% to about 100%, about 60% to about 100%, about 70% to about100%, about 80% to about 100%, about 10% to about 90%, about 20% toabout 90%, about 30% to about 90%, about 40% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 10% toabout 80%, about 20% to about 80%, about 30% to about 80%, about 40% toabout 80%, about 50% to about 80%, or about 60% to about 80%, about 10%to about 70%, about 20% to about 70%, about 30% to about 70%, about 40%to about 70%, or about 50% to about 70%, and capable of increasing thelevels of IL-10 released from a Th2 cell in a range from, e.g., about10% to about 100%, about 20% to about 100%, about 30% to about 100%,about 40% to about 100%, about 50% to about 100%, about 60% to about100%, about 70% to about 100%, about 80% to about 100%, about 10% toabout 90%, about 20% to about 90%, about 30% to about 90%, about 40% toabout 90%, about 50% to about 90%, about 60% to about 90%, about 70% toabout 90%, about 10% to about 80%, about 20% to about 80%, about 30% toabout 80%, about 40% to about 80%, about 50% to about 80%, or about 60%to about 80%, about 10% to about 70%, about 20% to about 70%, about 30%to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of aninflammation inducing molecule. In an aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of reducing the levels of substance P (SP), calcitoningene-related peptide (CGRP), glutamate, or a combination thereof. Inother aspects of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof SP, CGRP, glutamate, or a combination thereof released from a sensoryneuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In yet otheraspects of this embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of reducing the levels of SP,CGRP, glutamate, or a combination thereof released from a sensory neuronin a range from, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

A therapeutic compound disclosed herein may have a log P valueindicating that the compound is soluble in an organic solvent. As usedherein, the term “log P value” refers to the logarithm (base 10) of thepartition coefficient (P) for a compound and is a measure oflipophilicity. Typically, P is defined as the ratio of concentrations ofa unionized compound in the two phases of a mixture of two immisciblesolvents at equilibrium. Thus, log P=Log 10 (P), where P=[solute inimmiscible solvent 1]/[solute in immiscible solvent 2]. With regard toorganic and aqueous phases, the log P value of a compound is constantfor any given pair of aqueous and organic solvents, and its value can bedetermined empirically by one of several phase-partitioning methodsknown to one skilled in the art including, e.g., a shake flask assay, aHPLC assay, and an interface between two immiscible electrolytesolutions (ITIES) assay.

In aspects of this embodiment, a therapeutic compound disclosed hereinmay have a log P value indicating that the compound is substantiallysoluble in an organic solvent. In aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value indicatingthat the compound is, e.g., at least 50% soluble in an organic solvent,at least 60% soluble in an organic solvent, at least 70% soluble in anorganic solvent, at least 80% soluble in an organic solvent, or at least90% soluble in an organic solvent. In aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value indicatingthat the compound is between, e.g., about 50% to about 100% soluble inan organic solvent, about 60% to about 100% soluble in an organicsolvent, about 70% to about 100% soluble in an organic solvent, about80% to about 100% soluble in an organic solvent, or about 90% to about100% soluble in an organic solvent.

In aspects of this embodiment, a therapeutic compound disclosed hereinmay have a log P value of, e.g., more than 1.1, more than 1.2, more than1.4, more than 1.6, more than 1.8, more than 2.0, more than 2.2, morethan 2.4, more than 2.6, more than 2.8, more than 3.0, more than 3.2,more than 3.4, or more than 3.6. In other aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value in therange of, e.g., between 1.8 and 4.0, between 2.0 and 4.0, between 2.1and 4.0, between 2.2 and 4.0, or between 2.3 and 4.0, between 2.4 and4.0, between 2.5 and 4.0, between 2.6 and 4.0, or between 2.8 and 4.0.In other aspects of this embodiment, a therapeutic compound disclosedherein may have a log P value in the range of, e.g., between 3.0 and4.0, or between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 and 4.0,between 3.4 and 4.0, between 3.5 and 4.0, or between 3.6 and 4.0. Instill other aspects of this embodiment, a therapeutic compound disclosedherein may have a log P value in the range of, e.g., between 2.0 and2.5, between 2.0 and 2.7, between 2.0 and 3.0, or between 2.2 and 2.5.

A therapeutic compound disclosed herein may have a polar surface areathat is hydrophobic. As used herein, the term “polar surface area”refers to the surface sum over all of the polar atoms in the structureof a compound and is a measure of hydrophobicity. Typically, these polaratoms include, e.g., oxygen, nitrogen, and their attached hydrogens. Inaspects of this embodiment, a therapeutic compound disclosed herein mayhave a polar surface area of, e.g., less than 8.0 nm², less than 7.0nm², less than 6.0 nm², less than 5.0 nm², less than 4.0 nm², or lessthan 3.0 nm². In other aspects of this embodiment, a therapeuticcompound disclosed herein may have a polar surface area in the range of,e.g., between 3.0 nm² and 6.5 nm², between 3.0 nm² and 6.0 nm², between3.0 nm² and 5.5 nm², between 3.0 nm² and 5.0 nm², between 3.0 nm² and4.5 nm², between 3.5 nm² and 6.5 nm², between 3.5 nm² and 6.0 nm²,between 3.5 nm² and 5.5 nm², between 3.5 nm² and 5.0 nm², between 3.5nm² and 4.5 nm², between 4.0 nm² and 6.5 nm², between 4.0 nm² and 6.0nm², between 4.0 nm² and 5.5 nm², or between 4.0 nm² and 5.0 nm²,between 4.0 nm² and 4.5 nm², or between 4.5 nm² and 5.5 nm². In yetother aspects of this embodiment, a therapeutic compound disclosedherein may have a polar surface area in the range of, e.g., between 2.0nm² and 6.5 nm², between 2.0 nm² and 6.0 nm², between 2.0 nm² and 5.5nm², between 2.0 nm² and 5.0 nm², between 2.0 nm² and 4.5 nm², between2.5 nm² and 6.5 nm², between 2.5 nm² and 6.0 nm², between 2.5 nm² and5.5 nm², between 2.5 nm² and 5.0 nm², or between 2.5 nm² and 4.5 nm².

A therapeutic compound disclosed herein may be a non-steroidalanti-inflammatory drug (NSAID). NSAIDs are a large group of therapeuticcompounds with analgesic, anti-inflammatory, and anti-pyreticproperties. NSAIDs reduce inflammation by blocking cyclooxygenase.NSAIDs include, without limitation, Aceclofenac, Acemetacin, Actarit,Alcofenac, Alminoprofen, Amfenac, Aloxipirin, Aminophenazone,Antraphenine, Aspirin, Azapropazone, Benorilate, Benoxaprofen,Benzydamine, Butibufen, Celecoxib, Chlorthenoxacin, Choline Salicylate,Clometacin, Dexketoprofen, Diclofenac, Diflunisal, Emorfazone,Epirizole; Etodolac, Etoricoxib, Feclobuzone, Felbinac, Fenbufen,Fenclofenac, Flurbiprofen, Glafenine, Hydroxylethyl salicylate,Ibuprofen, Indometacin, Indoprofen, Ketoprofen, Ketorolac, Lactylphenetidin, Loxoprofen, Lumiracoxib, Mefenamic acid, Meloxicam,Metamizole, Metiazinic acid, Mofebutazone, Mofezolac, Nabumetone,Naproxen, Nifenazone, Niflumic acid, Oxametacin, Phenacetin, Pipebuzone,Pranoprofen, Propyphenazone, Proquazone, Protizinic acid, Rofecoxib,Salicylamide, Salsalate, Sulindac, Suprofen, Tiaramide, Tinoridine,Tolfenamic acid, Valdecoxib, and Zomepirac.

NSAIDs may be classified based on their chemical structure or mechanismof action. Non-limiting examples of NSAIDs include a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1)inhibitor, and a selective cyclooxygenase 2 (COX 2) inhibitor. A NSAIDmay be a profen. Examples of a suitable salicylate derivative NSAIDinclude, without limitation, Acetylsalicylic acid (asprin), Diflunisal,and Salsalate. Examples of a suitable p-amino phenol derivative NSAIDinclude, without limitation, Paracetamol and Phenacetin. Examples of asuitable propionic acid derivative NSAID include, without limitation,Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen,Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin,Pranoprofen, and Suprofen. Examples of a suitable acetic acid derivativeNSAID include, without limitation, Aceclofenac, Acemetacin, Actarit,Alcofenac, Amfenac, Clometacin, Diclofenac, Etodolac, Felbinac,Fenclofenac, Indometacin, Ketorolac, Metiazinic acid, Mofezolac,Nabumetone, Naproxen, Oxametacin, Sulindac, and Zomepirac. Examples of asuitable enolic acid (Oxicam) derivative NSAID include, withoutlimitation, Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, andTenoxicam. Examples of a suitable fenamic acid derivative NSAID include,without limitation, Flufenamic acid, Mefenamic acid, Meclofenamic acid,and Tolfenamic acid. Examples of a suitable selective COX-2 inhibitorsinclude, without limitation, Celecoxib, Etoricoxib, Firocoxib,Lumiracoxib, Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib.

A therapeutic compound disclosed herein may be a PPARγ agonist. Examplesof a suitable PPARγ agonist include, without limitation, Benzbromarone,a cannabidiol, Cilostazol, Curcumin, Delta(9)-tetrahydrocannabinol,glycyrrhetinic acid, Indomethacin, Irbesartan, Monascin, mycophenolicacid, Resveratrol, 6-shogaol, Telmisartan, a thiazolidinedione likeRosiglitazone, Pioglitazone, and Troglitazone, a NSAID, and a fibrate.Other suitable PPARγ agonists are described in Masson andCaumont-Bertrand, PPAR Agonist Compounds, Preparation and Uses, US2011/0195993, which is hereby incorporated by reference in its entirety.

A therapeutic compound disclosed herein may be a nuclear receptorbinding agent. Examples of a suitable nuclear receptor binding agentinclude, without limitation, a Retinoic Acid Receptor (RAR) bindingagent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor(LXR) binding agent and a Vitamin D binding agent.

A therapeutic compound disclosed herein may be an anti-hyperlipidemicagent. There are several classes of anti-hyperlipidemic agents (alsoknown as hypolipidemic agents). They may differ in both their impact onthe cholesterol profile and adverse effects. For example, some may lowerLDL, while others may preferentially increase HDL. Clinically, thechoice of an agent will depend on the cholesterol profile of anindividual, cardiovascular risk of an individual, and/or the liver andkidney functions of an individual. Examples of a suitableanti-hyperlipidemic agent include, without limitation, a fibrate, astatin, a tocotrienol, a niacin, a bile acid sequestrants (resin), acholesterol absorption inhibitor, a pancreatic lipase inhibitor, and asympathomimetic amine.

A therapeutic compound disclosed herein may be a fibrate. Fibrates are aclass of amphipathic carboxylic acids with lipid level modifyingproperties. These therapeutic compounds are used for a range ofmetabolic disorders. One non-limiting use is as an anti-hyperlipidemicagent where it may lower levels of, e.g., triglycerides and LDL as wellas increase levels of HDL. Examples of a suitable fibrate include,without limitation, Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil,and Fenofibrate.

A therapeutic compound disclosed herein may be a statin. Statins (orHMG-CoA reductase inhibitors) are a class of therapeutic compounds usedto lower LDL and/or cholesterol levels by inhibiting the enzyme HMG-CoAreductase, which plays a central role in the production of cholesterolin the liver. To compensate for the decreased cholesterol availability,synthesis of hepatic LDL receptors is increased, resulting in anincreased clearance of LDL particles from the blood. Examples of asuitable statin include, without limitation, Atorvastatin, Fluvastatin,Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, and Simvastatin.

A therapeutic compound disclosed herein may be a tocotrienol.Tocotrienols are another class of HMG-CoA reductase inhibitors and maybe used to lower LDL and/or cholesterol levels by inducing hepatic LDLreceptor up-regulation and/or decreasing plasma LDL levels. Examples ofa suitable tocotrienol include, without limitation, a γ-tocotrienol anda δ-tocotrienol.

A therapeutic compound disclosed herein may be a niacin. Niacins are aclass of therapeutic compounds with lipid level modifying properties.For example, a niacin may lower LDL by selectively inhibiting hepaticdiacyglycerol acyltransferase 2, reduce triglyceride synthesis, and VLDLsecretion through a receptor HM74 and HM74A or GPR109A. Thesetherapeutic compounds are used for a range of metabolic disorders. Onenon-limiting use is as an anti-hyperlipidemic agent where it may inhibitthe breakdown of fats in adipose tissue. Because a niacin blocks thebreakdown of fats, it causes a decrease in free fatty acids in the bloodand, as a consequence, decreases the secretion of VLDL and cholesterolby the liver. By lowering VLDL levels, a niacin may also increase thelevel of HDL in blood. Examples of a suitable niacin include, withoutlimitation, acipimox, niacin, nicotinamide, and vitamin B3.

A therapeutic compound disclosed herein may be a bile acid sequestrant.Bile acid sequestrants (also known as resins) are a class of therapeuticcompounds used to bind certain components of bile in thegastrointestinal tract. They disrupt the enterohepatic circulation ofbile acids by sequestering them and preventing their reabsorption fromthe gut. Bile acid sequestrants are particularly effective for loweringLDL and cholesterol by sequestering the cholesterol-containing bileacids released into the intestine and preventing their reabsorption fromthe intestine. In addition, a bile acid sequestrant may also raise HDLlevels. Examples of a suitable bile acid sequestrant include, withoutlimitation, Cholestyramine, Colesevelam, and Colestipol.

A therapeutic compound disclosed herein may be a cholesterol absorptioninhibitor. Cholesterol absorption inhibitors are a class of therapeuticcompounds that inhibits the absorption of cholesterol from theintestine. Decreased cholesterol absorption leads to an upregulation ofLDL-receptors on the surface of cells and an increased LDL-cholesteroluptake into these cells, thus decreasing levels of LDL in the bloodplasma. Examples of a suitable cholesterol absorption inhibitor include,without limitation, Ezetimibe, a phytosterol, a sterol and a stanol.

A therapeutic compound disclosed herein may be a fat absorptioninhibitor. Fat absorption inhibitors are a class of therapeuticcompounds that inhibits the absorption of fat from the intestine.Decreased fat absorption reduces caloric intake. In one aspect, a fatabsorption inhibitor inhibits pancreatic lipase, an enzyme that breaksdown triglycerides in the intestine. Examples of a suitable fatabsorption inhibitor include, without limitation, Orlistat.

A therapeutic compound disclosed herein may be a sympathomimetic amine.Sympathomimetic amines are a class of therapeutic compounds that mimicthe effects of transmitter substances of the sympathetic nervous systemsuch as catecholamines, epinephrine (adrenaline), norepinephrine(noradrenaline), and/or dopamine. A sympathomimetic amine may act as anα-adrenergic agonist, a β-adrenergic agonist, a dopaminergic agonist, amonoamine oxidase (MAO) inhibitor, and a COMT inhibitor. Suchtherapeutic compounds, among other things, are used to treat cardiacarrest, low blood pressure, or even delay premature labor. Examples of asuitable sympathomimetic amine include, without limitation, Clenbuterol,Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine,phenylephrine, isoproterenol, dobutamine, methylphenidate,lisdexamfetamine, cathine, cathinone, methcathinone, cocaine,benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV),4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine.

A therapeutic compound disclosed herein may be an ester of a therapeuticcompound. An ester of a therapeutic compound increases the log P valuerelative to the same therapeutic compound, but without the estermodification. An ester group may be attached to a therapeutic compoundby, e.g., a carboxylic acid or hydroxyl functional group present of thetherapeutic compound. An ester of a therapeutic compound may have anincreased hydrophobicity, and as such, may be dissolved in a reducedvolume of solvent disclosed herein. In some instances, an ester of atherapeutic compound may be combined directly with an adjuvant disclosedherein, thereby eliminating the need of a solvent. An ester of atherapeutic compound may enable the making of a pharmaceuticalcomposition disclosed herein, in situations where a non-esterified formof the same therapeutic compound is otherwise immiscible in a solventdisclosed herein. An ester of a therapeutic compound may still bedelivered in a manner that more effectively normalizes lipid levelsand/or inhibits a pro-inflammatory response as long as the compound iscombined with an adjuvant disclosed herein. In one embodiment, atherapeutic compound may be reacted with ethyl ester in order to form anethyl ester of the therapeutic compound.

In another embodiment, a pharmaceutical composition disclosed hereindoes not comprise a pharmaceutically-acceptable solvent disclosedherein. In an aspect of this embodiment, a pharmaceutical compositioncomprises a therapeutic compound and a pharmaceutically-acceptableadjuvant, but does not comprise a pharmaceutically-acceptable solventdisclosed herein.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in an amount sufficient to allow customary administration to anindividual. In aspects of this embodiment, a pharmaceutical compositiondisclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg,at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg,at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of atherapeutic compound. In other aspects of this embodiment, apharmaceutical composition disclosed herein may be, e.g., at least 5 mg,at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg,at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of atherapeutic compound. In yet other aspects of this embodiment, apharmaceutical composition disclosed herein may be in the range of,e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg,about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mgto about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg toabout 1,500 mg. In still other aspects of this embodiment, apharmaceutical composition disclosed herein may be in the range of,e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg,about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mgto about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg,about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg toabout 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000mg, or about 5 mg to about 250 mg.

Aspects of the present specification disclose, in part, apharmaceutically-acceptable solvent. A solvent is a liquid, solid, orgas that dissolves another solid, liquid, or gaseous (the solute),resulting in a solution. Solvents useful in the pharmaceuticalcompositions disclosed herein include, without limitation, apharmaceutically-acceptable polar aprotic solvent, apharmaceutically-acceptable polar protic solvent and apharmaceutically-acceptable non-polar solvent. Apharmaceutically-acceptable polar aprotic solvent includes, withoutlimitation, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate,acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO). A pharmaceutically-acceptable polar protic solventincludes, without limitation, acetic acid, formic acid, ethanol,n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol,n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water.A pharmaceutically-acceptable non-polar solvent includes, withoutlimitation, pentane, cyclopentane, hexane, cyclohexane, benzene,toluene, 1,4-Dioxane, chloroform, n-methyl-pyrrilidone (NMP), anddiethyl ether.

A pharmaceutical composition disclosed herein may comprise a solvent inan amount sufficient to dissolve a therapeutic compound disclosedherein. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may comprise a solvent in an amount of,e.g., less than about 90% (v/v), less than about 80% (v/v), less thanabout 70% (v/v), less than about 65% (v/v), less than about 60% (v/v),less than about 55% (v/v), less than about 50% (v/v), less than about45% (v/v), less than about 40% (v/v), less than about 35% (v/v), lessthan about 30% (v/v), less than about 25% (v/v), less than about 20%(v/v), less than about 15% (v/v), less than about 10% (v/v), less thanabout 5% (v/v), or less than about 1% (v/v). In other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise asolvent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v),about 1% (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about 1% (v/v)to 50% (v/v), about 1% (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v),about 1% (v/v) to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v)to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v),about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v)to 50% (v/v), about 4% (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v),about 4% (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v)to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v),about 6% (v/v) to 20% (v/v), about 6% (v/v) to 10% (v/v), about 8% (v/v)to 50% (v/v), about 8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v),about 8% (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8%(v/v) to 12% (v/v).

In one embodiment, a solvent may comprise a pharmaceutically-acceptablealcohol. As used herein, the term “alcohol” refers to an organicmolecule comprising a hydroxyl functional group (—OH) bond to a carbonatom, where the carbon atom is saturated. In aspects of this embodiment,the alcohol may be, e.g., a C₂₋₄ alcohol, a C₁₋₄ alcohol, a C₁₋₅alcohol, a C₁₋₇ alcohol, a C₁₋₁₀ alcohol, a C₁₋₁₅ alcohol, or a C₁₋₂₀alcohol. In other aspects of this embodiment, an alcohol may be, e.g., aprimary alcohol, a secondary alcohol, or a tertiary alcohol. In otheraspects of this embodiment, an alcohol may be, e.g., an acyclic alcohol,a monohydric alcohol, a polyhydric alcohol (also known as a polyol orsugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol,or a combination thereof. Examples of a monohydric alcohol include,without limitation, methanol, ethanol, propanol, butanol, pentanol, and1-hexadecanol. Examples of a polyhydric alcohol include, withoutlimitation, glycol, glycerol, arabitol, erythritol, xylitol, maltitol,sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol),and isomalt. Examples of an unsaturated aliphatic alcohol include,without limitation, prop-2-ene-1-ol, 3,7-dimethylocta-2,6-dien-1-ol, andprop-2-in-1-ol. Examples of an alicyclic alcohol include, withoutlimitation, cyclohexane-1,2,3,4,5,6-hexol and2-(2-propyl)-5-methyl-cyclohexane-1-ol.

In another embodiment, a solvent may comprise an ester ofpharmaceutically-acceptable alcohol and an acid. Suitablepharmaceutically-acceptable alcohols include the ones disclosed herein.Suitable acids include, without limitation, acetic acid, butaric acid,and formic acid. An ester of an alcohol and an acid include, withoutlimitation, methyl acetate, methyl buterate, methyl formate, ethylacetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate,propyl formate, butyl acetate, butyl buterate, butyl formate, isobutylacetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentylbuterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate,and 1-hexadecyl formate.

In another embodiment, a solvent may comprise apharmaceutically-acceptable polyethylene glycol (PEG) polymer. PEGpolymers, also known as polyethylene oxide (PEO) polymers orpolyoxyethylene (POE) polymers, are prepared by polymerization ofethylene oxide and are commercially available over a wide range ofmolecular weights from 100 g/mol to 10,000,000 g/mol. PEG polymers witha low molecular mass are liquids or low-melting solids, whereas PEGpolymers of a higher molecular mass are solids. A PEG polymer include,without limitation, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300,PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000,PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700,PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750,PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000,PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500,PEG 10,000, PEG 11,000, PEG 12,000, PEG 13,000, PEG 14,000, PEG 15,000,PEG 16,000, PEG 17,000, PEG 18,000, PEG 19,000, or PEG 20,000.

In another embodiment, a solvent may comprise apharmaceutically-acceptable glyceride. Glycerides comprise a substitutedglycerol, where one, two, or all three hydroxyl groups of the glycerolare each esterified using a fatty acid to produce monoglycerides,diglycerides, and triglycerides, respectively. In these compounds, eachhydroxyl groups of glycerol may be esterified by different fatty acids.Additionally, glycerides may be acetylated to produce acetylatedmonoglycerides, acetylated diglycerides, and acetylated triglycerides.

In one embodiment, a solvent may comprise a pharmaceutically-acceptablesolid solvent. Solid solvents may be useful in the manufacture of asolid dose formulation of a pharmaceutical composition disclosed herein.Typically, a solid solvent is melted in order to dissolve a therapeuticcompound. A pharmaceutically-acceptable solid solvent includes, withoutlimitation, Menthol and PEG polymers above about 20,000 g/mol.

Aspects of the present specification disclose, in part, apharmaceutically-acceptable adjuvant. An adjuvant is a pharmacologicalagent that modifies the effect of other agents, such as, e.g., atherapeutic compound disclosed herein. In addition, an adjuvantdisclosed herein may be used as a solvent that dissolves a therapeuticcompound disclosed herein, forming a adjuvant solution. An adjuvantdisclosed herein facilitates delivery of a therapeutic compound in amanner that more effectively normalizes lipid levels and/or inhibits apro-inflammatory response. In one embodiment, an adjuvant disclosedherein facilitates the delivery of a therapeutic compound disclosedherein into macrophages.

A pharmaceutical composition disclosed herein may comprise apharmaceutically-acceptable adjuvant in an amount sufficient to mix witha solution disclosed herein or an emulsion disclosed herein. In otheraspects of this embodiment, a pharmaceutical composition disclosedherein may comprise an adjuvant in an amount of, e.g., at least 10%(v/v), at least 20% (v/v), at least 30% (v/v), at least 35% (v/v), atleast 40% (v/v), at least 45% (v/v), at least 50% (v/v), at least 55%(v/v), at least 60% (v/v), at least 65% (v/v), at least 70% (v/v), atleast 75% (v/v), at least 80% (v/v), at least 85% (v/v), at least 90%(v/v), at least 95% (v/v), or at least 99% (v/v). In other aspects ofthis embodiment, a pharmaceutical composition disclosed herein maycomprise an adjuvant in an amount in a range of, e.g., about 30% (v/v)to about 99% (v/v), about 35% (v/v) to about 99% (v/v), about 40% (v/v)to about 99% (v/v), about 45% (v/v) to about 99% (v/v), about 50% (v/v)to about 99% (v/v), about 30% (v/v) to about 98% (v/v), about 35% (v/v)to about 98% (v/v), about 40% (v/v) to about 98% (v/v), about 45% (v/v)to about 98% (v/v), about 50% (v/v) to about 98% (v/v), about 30% (v/v)to about 95% (v/v), about 35% (v/v) to about 95% (v/v), about 40% (v/v)to about 95% (v/v), about 45% (v/v) to about 95% (v/v), or about 50%(v/v) to about 95% (v/v). In yet other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise an adjuvant inan amount in a range of, e.g., about 70% (v/v) to about 97% (v/v), about75% (v/v) to about 97% (v/v), about 80% (v/v) to about 97% (v/v), about85% (v/v) to about 97% (v/v), about 88% (v/v) to about 97% (v/v), about89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97% (v/v), about75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96% (v/v), about85% (v/v) to about 96% (v/v), about 88% (v/v) to about 96% (v/v), about89% (v/v) to about 96% (v/v), about 90% (v/v) to about 96% (v/v), about75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93% (v/v), about85% (v/v) to about 93% (v/v), about 88% (v/v) to about 93% (v/v), about89% (v/v) to about 93% (v/v), or about 90% (v/v) to about 93% (v/v).

In one embodiment, an adjuvant may be a pharmaceutically-acceptablelipid. A lipid may be broadly defined as a hydrophobic or amphiphilicsmall molecule. The amphiphilic nature of some lipids allows them toform structures such as vesicles, liposomes, or membranes in an aqueousenvironment. Non-limiting examples, of lipids include fatty acids,glycerolipids (like monoglycerides, diglycerides, and triglycerides),phospholipids, sphingolipids, sterol lipids, prenol lipids,saccharolipids, and polyketides. A pharmaceutical composition disclosedherein may comprise a lipid such as, e.g. an oil, an oil-based liquid, afat, a fatty acid, a wax, a fatty acid ester, a fatty acid salt, a fattyalcohol, a glyceride (mono-, di- or tri-glyceride), a phospholipids, aglycol ester, a sucrose ester, a glycerol oleate derivative, a mediumchain triglyceride, or a mixture thereof.

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically-acceptable fatty acid. A fatty acid comprises acarboxylic acid with a long unbranched hydrocarbon chain which may beeither saturated or unsaturated. Thus arrangement confers a fatty acidwith a polar, hydrophilic end, and a nonpolar, hydrophobic end that isinsoluble in water. Most naturally occurring fatty acids have ahydrocarbon chain of an even number of carbon atoms, typically between 4and 24 carbons, and may be attached to functional groups containingoxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fattyacids may have a hydrocarbon chain of any number of carbon atoms frombetween 3 and 40 carbons. Where a double bond exists, there is thepossibility of either a cis or a trans geometric isomerism, whichsignificantly affects the molecule's molecular configuration. Cis-doublebonds cause the fatty acid chain to bend, an effect that is morepronounced the more double bonds there are in a chain. Most naturallyoccurring fatty acids are of the cis configuration, although the transform does exist in some natural and partially hydrogenated fats andoils. Examples of fatty acids include, without limitation, Capryllicacid (8:0), pelargonic acid (9:0), Capric acid (10:0), Undecylic acid(11:0), Lauric acid (12:0), Tridecylic acid (13:0), Myristic acid(14:0), Myristoleic acid (14:1), Pentadecyclic acid (15:0), Palmiticacid (16:0), Palmitoleic acid (16:1), Sapienic acid (16:1), Margaricacid (17:0), Stearic acid (18:0), Oleic acid (18:1), Elaidic acid(18:1), Vaccenic acid (18:1), Linoleic acid (18:2), Linoelaidic acid(18:2), α-Linolenic acid (18:3), γ-Linolenic acid (18:3), Stearidonicacid (18:4), Nonadecylic acid (19:0), Arachidic acid (20:0), Eicosenoicacid (20:1), Dihomo-γ-linolenic acid (20:3), Mead acid (20:3),Arachidonic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosylic acid(21:0), Behenic acid (22:0), Erucic acid (22:1), Docosahexaenoic acid(22:6), Tricosylic acid (23:0), Lignoceric acid (24:0), Nervonic acid(24:1), Pentacosylic acid (25:0), Cerotic acid (26:0), Heptacosylic acid(27:0), Montanic acid (28:0), Nonacosylic acid (29:0), Melissic acid(30:0), Henatriacontylic acid (31:0), Lacceroic acid (32:0), Psyllicacid (33:0), Geddic acid (34:0), Ceroplastic acid (35:0), andHexatriacontylic acid (36:0).

In an embodiment, an adjuvant may be a pharmaceutically-acceptablesaturated or unsaturated fatty acid. In aspects of this embodiment, asaturated or unsaturated fatty acid comprises, e.g., at least 8, atleast 10, at least 12, at least 14, at least 16, at least 18, at least20, at least 22, at least 24, at least 26, at least 28, or at least 30carbon atoms, In other aspects of this embodiment, a saturated orunsaturated fatty acid comprises, e.g., between 4 and 24 carbon atoms,between 6 and 24 carbon atoms, between 8 and 24 carbon atoms, between 10and 24 carbon atoms, between 12 and 24 carbon atoms, between 14 and 24carbon atoms, or between 16 and 24 carbon atoms, between 4 and 22 carbonatoms, between 6 and 22 carbon atoms, between 8 and 22 carbon atoms,between 10 and 22 carbon atoms, between 12 and 22 carbon atoms, between14 and 22 carbon atoms, or between 16 and 22 carbon atoms, between 4 and20 carbon atoms, between 6 and 20 carbon atoms, between 8 and 20 carbonatoms, between 10 and 20 carbon atoms, between 12 and 20 carbon atoms,between 14 and 20 carbon atoms, or between 16 and 20 carbon atoms. Ifunsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 ormore, 4 or more, 5 or more, or 6 or more double bonds.

In aspects of this embodiment, a pharmaceutically-acceptable saturatedor unsaturated fatty acid is liquid at room temperature. The meltingpoint of a fatty acid is largely determined by the degree ofsaturation/unsaturation of the hydrocarbon chain. In aspects of thisembodiment, a saturated or unsaturated fatty acid has a melting pointtemperature of, e.g., 20° C. or below, 15° C. or below, 10° C. or below,5° C. or below, 0° C. or below, −5° C. or below, −10° C. or below, −15°C. or below, or −20° C. or below. In other aspects of this embodiment, asaturated or unsaturated fatty acid has a melting point temperature inthe range of, e.g., about −20° C. to about 20° C., about −20° C. toabout 18° C., about −20° C. to about 16° C., about −20° C. to about 12°C., about −20° C. to about 8° C., about −20° C. to about 4° C., about−20° C. to about 0° C., about −15° C. to about 20° C., about −15° C. toabout 18° C., about −15° C. to about 16° C., about −15° C. to about 12°C., about −15° C. to about 8° C., about −15° C. to about 4° C., about−15° C. to about 0° C.

In another embodiment, an adjuvant may comprise one kind ofpharmaceutically-acceptable fatty acid. In aspects of this embodiment,an adjuvant may comprise only palmitic acid, only stearic acid, onlyoleic acid, only linoleic acid, or only linolenic acid.

In another embodiment, an adjuvant may comprise a plurality of differentpharmaceutically-acceptable fatty acids. In aspects of this embodiment,an adjuvant may comprise, e.g., two or more different fatty acids, threeor more different fatty acids, four or more different fatty acids, fiveor more different fatty acids, or six or more different fatty acids.

In other aspects of this embodiment, an adjuvant may comprise two ormore different pharmaceutically-acceptable fatty acids including atleast palmitic acid, stearic acid, oleic acid, linoleic acid and/orlinolenic acid, and any combination thereof. In other aspects of thisembodiment, an adjuvant may comprise a ratio of palmitic acid and/orstearic acid and/or oleic acid:linolenic acid and/or linoleic acid of,e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least15:1, or at least 20:1. In yet other aspects of this embodiment, anadjuvant may comprise a ratio of palmitic acid and/or stearic acidand/or oleic acid:linolenic acid and/or linoleic acid in a range of,e.g., about 1:1 to about 20:1, about 2:1 to about 15:1, about 4:1 toabout 12:1, or about 6:1 to about 10:1.

In other aspects of this embodiment, an adjuvant may comprise four ormore different pharmaceutically-acceptable fatty acids including atleast palmitic acid, stearic acid, oleic acid, linoleic acid and/orlinolenic acid, and any combination thereof. In other aspects of thisembodiment, an adjuvant may comprise a ratio of palmitic acid:stearicacid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, 8:8:1:1,7:7:1:1, 6:6:1:1, 5:5:1:1, 4:4:1:1, 3:3:1:1, 2:2:1:1, or 1:1:1:1. Inother aspects of this embodiment, an adjuvant may comprise a ratio ofpalmitic acid; stearic acid:linolenic acid:linoleic acid in a range of,e.g., about 10:10:1:1 to about 6:6:1:1, about 8:8:1:1 to about 4:4:1:1,or about 5:5:1:1 to about 1:1:1:1.

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically-acceptable omega fatty acid. Non-limiting examplesof an omega fatty acid include omega-3, omega-6, and omega-9. Omega-3fatty acids (also known as n-3 fatty acids or ω-3 fatty acids) are afamily of essential unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-3 position, that is, the third bond,counting from the methyl end of the fatty acid. The omega-3 fatty acidsare “essential” fatty acids because they are vital for normal metabolismand cannot be synthesized by the human body. An omega-3 fatty acidincludes, without limitation, Hexadecatrienoic acid (16:3), α-Linolenicacid (18:3), Stearidonic acid (18:4), Eicosatrienoic acid (20:3),Eicosatetraenoic acid (20:4), Eicosapentaenoic acid (20:5),Heneicosapentaenoic acid (21:5), Docosapentaenoic acid (22:5),Clupanodonic acid (22:5), Docosahexaenoic acid (22:6),Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid (Nisinic acid)(24:6).

Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids)are a family of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-6 position, that is, the sixth bond,counting from the methyl end of the fatty acid. An omega-6 fatty acidincludes, without limitation, Linoleic acid (18:2), Gamma-linolenic acid(18:3), Calendic acid (18:3), Eicosadienoic acid (20:2),Dihomo-gamma-linolenic acid (20:3), Arachidonic acid (20:4),Docosadienoic acid (22:2), Adrenic acid (22:4), Docosapentaenoic acid(22:5), Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid(24:5). Omega-9 fatty acids (also known as n-9 fatty acids or ω-9 fattyacids) are a family of unsaturated fatty acids that have in common afinal carbon-carbon double bond in the n-9 position, that is, the ninthbond, counting from the methyl end of the fatty acid. An omega-9 fattyacid includes, without limitation, oleic acid (18:1), Elaidic acid(18:1), Eicosenoic acid (20:1), Mead acid (20:3), Erucic acid (22:1),and Nervonic acid (24:1).

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically-acceptable oil. An oil includes any fatty acidthat is liquid at normal room temperature, such as, e.g. about 20° C. Incontrast, a fat includes any fatty acid that is solid at normal roomtemperature, such as, e.g. about 20° C. An oil suitable as a lipiduseful in the pharmaceutical compositions disclosed herein, may be anatural oil or a vegetable oil. Examples of suitable natural oilsinclude, without limitation, mineral oil, triacetin, ethyl oleate, ahydrogenated natural oil, or a mixture thereof. Examples of suitablevegetable oils include, without limitation, almond oil, arachis oil,avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseedoil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seedoil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil,safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnutoil, wheat germ oil, or a mixture thereof. Each of these oils iscommercially available from a number of sources well recognized by thoseskilled in the art.

An oil is typically a mixture of various fatty acids. For example,Rapeseed oil, obtained from the seeds of Brassica napus, includes bothomega-6 and omega-3 fatty acids in a ratio of about 2:1. As anotherexample, linseed oil, obtained from the seeds of Linum usitatissimum,includes abut 7% palmitic acid, about 3.4-4.6% stearic acid, about18.5-22.6% oleic acid, about 14.2-17% linoleic acid, and about51.9-55.2% α-linolenic acid. In aspects of this embodiment, apharmaceutical composition comprises an oil including at least twodifferent fatty acids, at least three different fatty acids, at leastfour different fatty acids, at least five different fatty acids, or atleast six different fatty acids.

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically-acceptable glycerolipid. Glycerolipids arecomposed mainly of mono-, di-, and tri-substituted glycerols. One groupof glycerolipids is the glycerides, where one, two, or all threehydroxyl groups of glycerol are each esterified using a fatty acid toproduce monoglycerides, diglycerides, and triglycerides, respectively.In these compounds, each hydroxyl groups of glycerol may be esterifiedby different fatty acids. Additionally, glycerides may be acetylated toproduce acetylated monoglycerides, acetylated diglycerides, andacetylated triglycerides. One group of glycerolipids is the glycerides,where one, two, or all three hydroxyl groups of glycerol have sugarresidues attached via a glycosidic linkage.

Aspects of the present specification disclose, in part, apharmaceutically-acceptable stabilizing agent. A stabilizing agentreduces or eliminates formation of esters of a therapeutic compound thatmay result as a unwanted reaction with the particular solvent used. Astabilizing agent include, without limitation, water, a sacrificial acidcomprising a fatty acid component and acetic acid, ethyl acetate, asodium acetate/acetic acid (E262), a monoglyceride, an acetylatedmonoglyceride, a diglyceride, an acetylated monoglyceride, an acetylateddiglyceride, a fatty acid, and a fatty acid salt.

In one embodiment, a pharmaceutically-acceptable stabilizing agent maycomprise a pharmaceutically-acceptable emulsifying agent. An emulsifyingagent (also known as an emulgent) is a substance that stabilizes anemulsion comprising a liquid dispersed phase and a liquid continuousphase by increasing its kinetic stability. Thus, in situations where thesolvent and adjuvant used to make a pharmaceutical composition disclosedherein are normally immiscible, an emulsifying agent disclosed herein isused to create a homogenous and stable emulsion. An emulsifying agentincludes, without limitation, a surfactant, a polysaccharide, a lectin,and a phospholipid.

In an aspect of this embodiment, an emulsifying agent may comprise asurfactant. As used hereon, the term “surfactant” refers to a natural orsynthetic amphiphilic compound. A surfactant can be non-ionic,zwitterionic, or ionic. Non-limiting examples of surfactants includepolysorbates like polysorbate 20 (TWEEN® 20), polysorbate 40 (TWEEN®40), polysorbate 60 (TWEEN® 60), polysorbate 61 (TWEEN® 61), polysorbate65 (TWEEN® 65), polysorbate 80 (TWEEN® 80), and polysorbate 81 (TWEEN®81); poloxamers (polyethylene-polypropylene copolymers), like Poloxamer124 (PLURONIC® L44), Poloxamer 181 (PLURONIC® L61), Poloxamer 182(PLURONIC® L62), Poloxamer 184 (PLURONIC® L64), Poloxamer 188 (PLURONIC®F68), Poloxamer 237 (PLURONIC® F87), Poloxamer 338 (PLURONIC® L108),Poloxamer 407 (PLURONIC® F127), polyoxyethyleneglycol dodecyl ethers,like BRIJ® 30, and BRIJ® 35; 2-dodecoxyethanol (LUBROL®-PX);polyoxyethylene octyl phenyl ether (TRITON® X-100); sodium dodecylsulfate (SDS); 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate(CHAPS);3-[(3-Cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate(CHAPSO); sucrose monolaurate; and sodium cholate. Other non-limitingexamples of surfactant excipients can be found in, e.g., Ansel, supra,(1999); Gennaro, supra, (2000); Hardman, supra, (2001); and Rowe, supra,(2003), each of which is hereby incorporated by reference in itsentirety.

In an aspect of this embodiment, an emulsifying agent may comprise apolysaccharide. Non-limiting examples of polysaccharides include guargum, agar, alginate, calgene, a dextran (like dextran 1K, dextran 4K,dextran 40K, dextran 60K, and dextran 70K), dextrin, glycogen, inulin,starch, a starch derivative (like hydroxymethyl starch, hydroxyethylstarch, hydroxypropyl starch, hydroxybutyl starch, and hydroxypentylstarch), hetastarch, cellulose, FICOLL, methyl cellulose (MC),carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (NEMC),hydroxypropyl methyl cellulose (HPMC); polyvinyl acetates (PVA);polyvinyl pyrrolidones (PVP), also known as povidones, having a K-valueof less than or equal to 18, a K-value greater than 18 or less than orequal to 95, or a K-value greater than 95, like PVP 12 (KOLLIDON® 12),PVP 17 (KOLLIDON® 17), PVP 25 (KOLLIDON® 25), PVP 30 (KOLLIDON® 30), PVP90 (KOLLIDON® 90); and polyethylene imines (PEI).

In an aspect of this embodiment, an emulsifying agent may comprise alectin. Lectins are sugar-binding proteins that are highly specific fortheir sugar moieties. Lectins may be classified according to the sugarmoiety that they bind to, and include, without limitation,mannose-binding lectins, galactose/N-acetylgalactosamine-bindinglectins, N-acetylgluxosamine-binding lectins, N-acetylneuramine-bindinglectins, N-acetylneuraminic acid-binding lectins, and fucose-bindinglectins. Non-limiting examples of surfactants include concanavain A,lentil lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairyvetch lectin, wheat germ agglutinin, elderberry lectin, Maackiaanurensis leukoagglutinin, Maackia anurensis hemoagglutinin, Ulexeuropaeus agglutinin, and Aleuria aurantia lectin.

In an aspect of this embodiment, an emulsifying agent may comprise aphospholipid. The structure of the phospholipid generally comprises ahydrophobic tail and a hydrophilic head and is amphipathic in nature.Most phospholipids contain a diglyceride, a phosphate group, and asimple organic molecule such as choline; one exception to this rule issphingomyelin, which is derived from sphingosine instead of glycerol.Phospholipids include, without limitation, diacylglycerides andphosphosphingolipids. Non-limiting examples of diacylglycerides includea phosphatidic acid (phosphatidate) (PA), a phosphatidylethanolamine(cephalin) (PE), a phosphatidylcholine (lecithin) (PC), aphosphatidylserine (PS), and a phosphoinositide includingphosphatidylinositol (PI), phosphatidylinositol phosphate (PIP),phosphatidylinositol bisphosphate (PIP2), and phosphatidylinositoltriphosphate (PIP3). Non-limiting examples of phosphosphingolipidsinclude a ceramide phosphorylcholine (sphingomyelin) (SPH), ceramidephosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramidephosphorylglycerol.

In one embodiment, a pharmaceutically-acceptable stabilizing agent doesnot comprise a pharmaceutically-acceptable emulsifying agent.

In another embodiment, a pharmaceutical composition does not comprise apharmaceutically-acceptable emulsifying agent.

The pharmaceutical compositions disclosed herein act as a deliverysystem that enable a therapeutic compound disclosed herein to be moreeffectively delivered or targeted to a cell type, tissue, organ, orregion of the body in a manner that more effectively normalizes lipidlevels and/or inhibits a pro-inflammatory response. This modulationand/or inhibition results in an improved treatment of a cardiovasculardisease. For example, a pharmaceutical composition disclosed herein mayfacilitate the delivery of a therapeutic compound disclosed herein intomacrophages. One possible mechanism that achieves this selectivebiodistribution is that the pharmaceutical compositions disclosed hereinmay be designed to take advantage of the activity of chylomicrons.Chylomicrons are relatively large lipoprotein particles having adiameter of 75 nm to 1,200 nm. Comprising triglycerides (85-92%),phospholipids (6-12%), cholesterol (1-3%) and apolipoproteins (1-2%),chylomicrons transport dietary lipids from the intestines to otherlocations in the body.

During digestion, fatty acids and cholesterol undergo processing in thegastrointestinal tract by the action of pancreatic juices includinglipases and emulsification with bile salts to generate micelles. Thesemicelles allow the absorption of lipid as free fatty acids by theabsorptive cells of the small intestine, known as enterocytes. Once inthe enterocytes, triglycerides and cholesterol are assembled intonascent chylomicrons. Nascent chylomicrons are primarily composed oftriglycerides (85%) and contain some cholesterol and cholesteryl esters.The main apolipoprotein component is apolipoprotein B-48 (APOB48). Thesenascent chylomicrons are released by exocytosis from enterocytes intolacteals, lymphatic vessels originating in the villi of the smallintestine, and are then secreted into the bloodstream at the thoracicduct's connection with the left subclavian vein.

While circulating in lymph and blood, chylomicrons exchange componentswith HDL. The HDL donates apolipoprotein C-II (APOC2) and apolipoproteinE (APOE) to the nascent chylomicron and thus converts it to a maturechylomicron (often referred to simply as “chylomicron”). APOC2 is thecofactor for lipoprotein lipase (LPL) activity. Once triglyceride storesare distributed, the chylomicron returns APOC2 to the HDL (but keepsAPOE), and, thus, becomes a chylomicron remnant, now only 30-50 nm.APOB48 and APOE are important to identify the chylomicron remnant in theliver for endocytosis and breakdown into lipoproteins (VLDL, LDL andHDL). These lipoproteins are processed and stored by competent cells,including, e.g., hepatocytes, adipocytes and macrophages. Thus, withoutwishing to be limited by any theory, upon oral administration of thepharmaceutical compositions disclosed herein are processed into micelleswhile in the gastrointestinal tract, absorbed by enterocytes andassembled into nascent chylomicrons, remain associated with chylomicronremnants taken up by the liver, and ultimately loaded into macrophages.

Aspects of the present specification disclose, in part, a method ofpreparing a pharmaceutical composition disclosed herein. A methoddisclosed herein comprises the step of contacting apharmaceutically-acceptable adjuvant disclosed herein with a therapeuticcompound disclosed herein under conditions which allow the therapeuticcompound to dissolve in the pharmaceutically-acceptable adjuvant,thereby forming a pharmaceutical composition disclosed herein.

Aspects of the present specification disclose, in part, a method ofpreparing a pharmaceutical composition disclosed herein. A methoddisclosed herein comprises the steps of a) contacting apharmaceutically-acceptable solvent disclosed herein with a therapeuticcompound disclosed herein under conditions which allow the therapeuticcompound to dissolve in the pharmaceutically-acceptable solvent, therebyforming a solution; and b) contacting the solution formed in step (a)with a pharmaceutically-acceptable adjuvant disclosed herein underconditions which allow the formation of a pharmaceutical composition.The methods of preparing disclosed herein may further comprise a step(c) of removing the pharmaceutically-acceptable solvent from thepharmaceutical composition.

The amount of a therapeutic compound that is contacted with thepharmaceutically-acceptable solvent in step (a) of the method may be inany amount desired. Factors used to determine the amount of atherapeutic compound used include, without limitation, the final amountthe therapeutic compound desired in the pharmaceutical composition, thedesired concentration of a therapeutic compound in the solution, thehydrophobicity of the therapeutic compound, the lipophobicity of thetherapeutic compound, the temperature under which the contacting step(a) is performed, and the time under which the contacting step (a) isperformed

The volume of a pharmaceutically-acceptable solvent used in step (a) ofthe method may be any volume desired. Factors used to determine thevolume of a pharmaceutically-acceptable solvent used include, withoutlimitation, the final amount of a pharmaceutical composition desired,the desired concentration of a therapeutic compound in the solution, thehydrophobicity of the therapeutic compound, and the lipophobicity of thetherapeutic compound.

In aspects of this embodiment, the amount of a therapeutic compound thatis contacted with the solvent in step (a) may be, e.g., at least 10 mg,at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg,at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, atleast 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, atleast 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg,at least 1,400 mg, or at least 1,500 mg. In other aspects of thisembodiment, the amount of a therapeutic compound that is contacted withthe solvent in step (a) may be in the range of, e.g., about 10 mg toabout 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg,about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mgto about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, orabout 1,000 mg to about 1,500 mg. In other aspects of this embodiment,the amount of a therapeutic compound that is dissolved in the solvent instep (a) may be in the range of, e.g., about 10 mg to about 250 mg,about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg toabout 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg toabout 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg,about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mgto about 1,000 mg, or about 200 mg to about 1,500 mg.

Step (a) may be carried out at room temperature, in order to allow atherapeutic compound to dissolve fully in thepharmaceutically-acceptable solvent. However, in other embodiments ofthe method, step (a) may be carried out at a temperature that is greaterthan room temperature, e.g., greater than 21° C., greater than 25° C.,greater than 30° C., greater than 35° C. or greater than 37° C. Incertain cases, Step (a) may be carried out at temperatures below roomtemperature, in order to allow a therapeutic compound to dissolve fullyin solvent. However, in other embodiments of the method, step (a) may becarried out at a temperature that is less than room temperature, e.g.,less than 10° C., greater than 5° C., greater than 0° C., greater than−10° C. or greater than −20° C. The contacting in Step (a) may comprisemixing the therapeutic compound and the pharmaceutically-acceptablesolvent, e.g., by stirring, inversion, sonication, or vortexing. Themixing may be carried out for, e.g., at least 1 second, at least 5seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds,at least 45 seconds, at least 60 seconds, or more, until the therapeuticcompound is fully dissolved in the solvent.

After contacting, the concentration of a therapeutic compound disclosedherein in the solution may be in any concentration desired. In aspectsof this embodiment, the concentration of a therapeutic compounddisclosed herein in the solution may be, e.g., at least 0.00001 mg/mL,at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, atleast 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL,at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500mg/mL, at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200mg/mL. In other aspects of this embodiment, the concentration of atherapeutic compound disclosed herein in the solution may be, e.g., atmost 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects ofthis embodiment, the concentration of a therapeutic compound disclosedherein in the solution may be in a range of, e.g., about 0.00001 mg/mLto about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL,about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL toabout 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mLto about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL,about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500mg/mL, about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to about1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750 mg/mL toabout 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to about 1,000 mg/mL,about 100 mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL,about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL,about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL toabout 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL,about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100mg/mL.

The volume of a pharmaceutically-acceptable adjuvant used in step (b) ofthe method may be any volume desired. Factors used to determine thevolume of a pharmaceutically-acceptable adjuvant used include, withoutlimitation, the final amount of a pharmaceutical composition desired,the desired concentration of a therapeutic compound in thepharmaceutical composition, the ratio of solvent:adjuvant used, and themiscibility of solvent and adjuvant.

In aspects of this embodiment, the ratio of solution:adjuvant may be,e.g., at least 5:1, at least 4:1, at least 3:1, at least 2:1, at least0:1, at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least1:10, at least 1:15, at least 1:20, or at least 1:25. In other aspectsof this embodiment, the ratio of solution:adjuvant may be in a range of,e.g., about 5:1 to about 1:25, about 4:1 to about 1:25, about 3:1 toabout 1:25, about 2:1 to about 1:25, about 0:1 to about 1:25, about 1:1to about 1:25, about 1:2 to about 1:25, about 1:3 to about 1:25, about1:4 to about 1:25, about 1:5 to about 1:25, about 5:1 to about 1:20,about 4:1 to about 1:20, about 3:1 to about 1:20, about 2:1 to about1:20, about 0:1 to about 1:20, about 1:1 to about 1:20, about 1:2 toabout 1:20, about 1:3 to about 1:20, about 1:4 to about 1:20, about 1:5to about 1:20, about 5:1 to about 1:15, about 4:1 to about 1:15, about3:1 to about 1:15, about 0:1 to about 1:15, about 2:1 to about 1:15,about 1:1 to about 1:15, about 1:2 to about 1:15, about 1:3 to about1:15, about 1:4 to about 1:15, about 1:5 to about 1:15, about 5:1 toabout 1:12, about 4:1 to about 1:12, about 3:1 to about 1:12, about 2:1to about 1:12, about 0:1 to about 1:12, about 1:1 to about 1:12, about1:2 to about 1:12, about 1:3 to about 1:12, about 1:4 to about 1:12,about 1:5 to about 1:12, about 1:6 to about 1:12, about 1:7 to about1:12, about 1:8 to about 1:12, about 5:1 to about 1:10, about 4:1 toabout 1:10, about 3:1 to about 1:10, about 2:1 to about 1:10, about 0:1to about 1:10, about 1:1 to about 1:10, about 1:2 to about 1:10, about1:3 to about 1:10, about 1:4 to about 1:10, about 1:5 to about 1:10,about 1:6 to about 1:10, about 1:7 to about 1:10, or about 1:8 to about1:10.

Step (b) may be carried out at room temperature, in order to allow thesolution comprising the therapeutic compound to form the pharmaceuticalcomposition. However, in other embodiments of the method, step (b) maybe carried out at a temperature that is greater than room temperature,e.g., greater than 21° C., greater than 25° C., greater than 30° C.,greater than 35° C. or greater than 37° C. In certain cases, Step (b)may be carried out at temperatures below room temperature, in order toallow a therapeutic compound to dissolve fully in apharmaceutically-acceptable solvent. However, in other embodiments ofthe method, step (b) may be carried out at a temperature that is lessthan room temperature, e.g., less than 10° C., greater than 5° C.,greater than 0° C., greater than −10° C. or greater than −20° C. Thecontacting in Step (b) may comprise mixing the solution and thepharmaceutically-acceptable adjuvant, e.g., by stirring, inversion,sonication, or vortexing. The mixing may be carried out for, e.g., atleast 1 second, at least 5 seconds, at least 10 seconds, at least 20seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds,or more, until the pharmaceutical composition is formed.

In Step (c), the solvent removal from a pharmaceutical composition maybe accomplished using one of a variety of procedures known in the art,including, without limitation, evaporation, dialyzation, distillation,lypholization, and filtration. These removal procedures may be doneunder conditions of ambient atmosphere, under low pressure, or under avacuum.

In one embodiment, Step (c) may result in the complete removal of apharmaceutically-acceptable solvent from the pharmaceutical compositiondisclosed herein. In aspects of this embodiment, Step (c) may result in,e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 93%, at least95%, at least 97%, or at least 99% removal of apharmaceutically-acceptable solvent from the pharmaceutical compositiondisclosed herein.

Step (c) is conducted at a temperature that allows for the evaporationof a pharmaceutically-acceptable solvent disclosed herein, and as such,an evaporation temperature is solvent dependant. Factors which influencean evaporation temperature of a solvent disclosed herein include,without limitation, the particular solvent used, the amount of solventpresent, the particular therapeutic compound present, the particularadjuvant present, the stability of the therapeutic compound present, thereactivity of the therapeutic compound present, the particularatmospheric pressure used, the time desired for complete evaporation.Generally, a pharmaceutical composition will require heating if theevaporation step is conducted at ambient pressure, e.g., 1 atm. However,under high vacuum conditions, the evaporation step may be conducted attemperatures below ambient temperature, e.g., less than 22° C.

In one embodiment, removal of solvent from the pharmaceuticalcomposition disclosed herein may be carried out at ambient atmosphericpressure and at a temperature above ambient temperature. In aspects ofthis embodiment, removal of solvent from the pharmaceutical compositiondisclosed herein may be carried out at ambient atmospheric pressure andat a temperature of, e.g., more than 25° C., more than 30° C., more than35° C., more than 40° C., more than 45° C., more than 50° C., more than55° C., more than 60° C., more than 65° C., more than 70° C., more than80° C., or more than 25° C. In other aspects of this embodiment, removalof solvent from the pharmaceutical composition disclosed herein may becarried out at ambient atmospheric pressure and at a temperature in arange of, e.g., about 25° C. to about 100° C., about 25° C. to about 95°C., about 25° C. to about 90° C., about 25° C. to about 85° C., about25° C. to about 80° C., about 25° C. to about 75° C., about 25° C. toabout 70° C., about 25° C. to about 65° C., or about 25° C. to about 60°C.

In another embodiment, removal of solvent from the pharmaceuticalcomposition disclosed herein may be carried out under vacuum and at atemperature below ambient temperature. In aspects of this embodiment,removal of solvent from the pharmaceutical composition disclosed hereinmay be carried out under vacuum and at a temperature of, e.g., less than20° C., less than 18° C., less than 16° C., less than 14° C., less than12° C., less than 10° C., less than 8° C., less than 6° C., less than 4°C., less than 2° C., or less than 0° C. In other aspects of thisembodiment, removal of solvent from the pharmaceutical compositiondisclosed herein may be carried out under vacuum and at a temperature ina range of, e.g., about −20° C. to about 20° C., about −20° C. to about18° C., about −20° C. to about 16° C., about −20° C. to about 14° C.,about −20° C. to about 12° C., about −20° C. to about 10° C., about −20°C. to about 8° C., about −20° C. to about 6° C., about −20° C. to about4° C., about −20° C. to about 2° C., about −20° C. to about 0° C., about−15° C. to about 20° C., about −10° C. to about 20° C., about −5° C. toabout 20° C., about 0° C. to about 20° C., about −10° C. to about 20°C., about −10° C. to about 18° C., about −10° C. to about 16° C., about−10° C. to about 14° C., about −10° C. to about 12° C., about −10° C. toabout 10° C., about −10° C. to about 8° C., about −10° C. to about 6°C., about −10° C. to about 4° C., about −10° C. to about 2° C., or about−10° C. to about 0° C.

The final concentration of a therapeutic compound disclosed herein in apharmaceutical composition disclosed herein may be of any concentrationdesired. In an aspect of this embodiment, the final concentration of atherapeutic compound in a pharmaceutical composition may be atherapeutically effective amount. In other aspects of this embodiment,the final concentration of a therapeutic compound in a pharmaceuticalcomposition may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL,at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, atleast 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In other aspectsof this embodiment, the concentration of a therapeutic compounddisclosed herein in the solution may be, e.g., at most 1,000 mg/mL, atmost 1,100 mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at most1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000mg/mL, or at most 3,000 mg/mL. In other aspects of this embodiment, thefinal concentration of a therapeutic compound in a pharmaceuticalcomposition may be in a range of, e.g., about 0.00001 mg/mL to about3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mLto about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL,about 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL toabout 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 250 mg/mLto about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL,about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750 mg/mL to about1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL toabout 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mLto about 1,000 mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL,about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mLto about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

A pharmaceutical composition produced using the methods disclosed hereinmay be a liquid formulation or a solid or semi-solid formulation. Aliquid formulation can be formed by using various lipids like oils ofother fatty acids that remain as liquids in the temperature rangedesired. In an embodiment, a pharmaceutical composition disclosed hereinis liquid at room temperature. In aspects of this embodiment, apharmaceutical composition disclosed herein may be formulated to be aliquid at a temperature of, e.g., about 25° C. or higher, about 23° C.or higher, about 21° C. or higher, about 19° C. or higher, about 17° C.or higher, about 15° C. or higher, about 12° C. or higher, about 10° C.or higher, about 8° C. or higher, about 6° C. or higher, about 4° C. orhigher, or about 0° C. or higher. In other aspects of this embodiment, apharmaceutical composition disclosed herein may be formulated to be aliquid at a temperature of, e.g.,

A solid or semi-solid formulation disclosed herein takes advantage ofthe different melting point temperatures of the various adjuvants likefatty acids. Formation of a solid or semi-solid dosage form can be bymodifying the respective concentrations of the fatty acids comprising apharmaceutical composition disclosed herein. For example, linolenic acidhas a melting point temperature (T_(m)) of about −11° C., linoleic acidhas a T_(m) of about −5° C., oleic acid has a T_(m) of about 16° C.,palmitic acid has a T_(m) of about 61-62° C., and Stearic acid has aT_(m) of about 67-72° C. Increasing the proportion(s) of palmitic,stearic or oleic acid would increase the overall melting temperature ofa composition, while, conversely, increasing the proportion(s) oflinoleic and linolenic acid would decrease the melting temperature of acomposition. Thus, by controlling the types and amounts of the adjuvantcomponents added, a pharmaceutical composition disclosed herein can bemade that is substantially solid or semi-solid at room temperature, butmelts when it is ingested, and reaches body temperature. The resultingmelted composition readily forms micelles which are absorbed by theintestine, assembled into chylomicrons, and ultimately absorbed bymacrophages. The solid dosage form may be a powder, granule, tablet,capsule or suppository.

In an embodiment, a pharmaceutical composition disclosed herein is solidat room temperature. In aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may be formulated to be a solid at atemperature of, e.g., about 35° C. or lower, about 33° C. or lower,about 31° C. or lower, about 29° C. or lower, about 27° C. or lower,about 25° C. or lower, about 23° C. or lower, about 21° C. or lower,about 19° C. or lower, about 17° C. or lower, about 15° C. or lower,about 12° C. or lower, about 10° C. or lower, about 8° C. or lower,about 6° C. or lower, v 4° C. or lower, or about 0° C. or lower.

In other aspects of this embodiment, a pharmaceutical compositiondisclosed has a melting point temperature of, e.g., 5° C. or higher, 10°C. or higher, 15° C. or higher, 22° C. or higher, 23° C. or higher, 24°C. or higher, 25° C. or higher, 26° C. or higher, 27° C. or higher, 28°C. or higher, 29° C. or higher, 30° C. or higher, 31° C. or higher, 32°C. or higher, 33° C. or higher, 34° C. or higher, or 35° C. or higher.In other aspects of this embodiment, a pharmaceutical compositiondisclosed has a melting point temperature in the range of, e.g., about5° C. to about 24° C., about 10° C. to about 24° C. about 22° C. toabout 24° C., about 23° C. to about 25° C., about 24° C. to about 26°C., about 25° C. to about 27° C., about 26° C. to about 28° C., about27° C. to about 29° C., about 28° C. to about 30° C., about 29° C. toabout 31° C., about 30° C. to about 32° C., about 31° C. to about 33°C., about 32° C. to about 34° C., or about 33° C. to about 35° C. Inother aspects of this embodiment, a pharmaceutical composition disclosedhas a melting point temperature in the range of, e.g., about 22° C. toabout 26° C., about 24° C. to about 28° C., about 26° C. to about 30°C., about 28° C. to about 32° C., or about 30° C. to about 34° C.

Aspects of the present specification disclose, in part, a method oftreating an individual with a cardiovascular disease. In one embodiment,the method comprises the step of administering to an individual in needthereof a pharmaceutical composition disclosed herein, whereinadministration reduces a symptom associated with the cardiovasculardisease, thereby treating the individual.

Aspects of the present specification disclose, in part, treating anindividual suffering from a cardiovascular disease. As used herein, theterm “treating,” refers to reducing or eliminating in an individual aclinical symptom of a cardiovascular disease; or delaying or preventingin an individual the onset of a clinical symptom of a cardiovasculardisease. For example, the term “treating” can mean reducing a symptom ofa condition characterized by a cardiovascular disease by, e.g., at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% at least95%, or at least 100%. The actual symptoms associated with acardiovascular disease are well known and can be determined by a personof ordinary skill in the art by taking into account factors, including,without limitation, the location of the cardiovascular disease, thecause of the cardiovascular disease, the severity of the cardiovasculardisease, and/or the tissue or organ affected by the cardiovasculardisease. Those of skill in the art will know the appropriate symptoms orindicators associated with a specific type of cardiovascular disease andwill know how to determine if an individual is a candidate for treatmentas disclosed herein.

Cardiovascular disease is any of a number of specific diseases thataffect the heart itself and/or the blood vessel system, especially theveins and arteries leading to and from the heart. Known and/orassociated causes of a cardiovascular disease include, withoutlimitation, unhealthy ratios of the two smallest lipoproteins LDL andHDL, hyperlipidemia, elevated blood glucose levels, upper normal andhigh blood pressure, Lp-PLA2, lipoprotein(a) and hyperhomocysteinemia.Symptoms of a cardiovascular disorder affecting the heart include,without limitation, chest pain, chest discomfort, and pain in one orboth arms, one or both shoulders, neck, jaw, or back, shortness ofbreath, dizziness, faster heartbeats, nausea, abnormal heartbeats,fatigue, and/or myocardial infarction. Symptoms of a cardiovasculardisorder affecting the brain include, without limitation, suddennumbness or weakness of the face, one or both arms, or one or both legs,sudden confusion or trouble speaking or understanding speech, suddentrouble seeing in one or both eyes, sudden dizziness, difficultywalking, or loss of balance or coordination, and/or sudden severeheadache with no known cause. Symptoms of a cardiovascular disorderaffecting one or both leg, pelvis, one or both arms, and/or shoulderinclude, without limitation, muscle pain, muscle cramp, cold sensationin one or both feet and/or toes, one or both hands and/or fingers,and/or numbness or weakness in one or both feet and/or toes, one or bothhands and/or fingers.

There are more than 60 types of cardiovascular disease including,without limitation, a hyperlipidemia, a coronary heart disease, anatherosclerosis, a peripheral vascular disease, a cardiomyopathy, avasculitis, an inflammatory heart disease, an ischemic heart disease, acongestive heart failure, a hypertensive heart disease, a valvular heartdisease, a hypertension, myocardial infarction, a diabetic cardiacconditions, an aneurysm; an embolism, a dissection, a pseudoaneurysm, avascular malformation, a vascular nevus, a thrombosis, a varicose vein,and a stroke.

In one embodiment, a cardiovascular disease comprises a hyperlipidemia.A hyperlipidemia (or hyperlipoproteinemia) refers to a conditioncharacterized by abnormally elevated levels of lipids and/orlipoproteins in the blood. Hyperlipidemias may be classified as familial(or primary) when caused by specific genetic abnormalities, acquired (orsecondary) when resulting from another underlying disorder, oridiopathic, when of unknown cause. Hyperlipidemias may also beclassified based on which types of lipids and/or lipoproteins areelevated. Non-limiting examples of a hyperlipidemia includedyslipidemia, hypercholesterolemia, hyperglyceridemia,hypertriglyceridemia, hyperlipoproteinemia, and hyperchylomicronemia,and combined hyperlipidemia. Hyperlipoproteinemia include, e.g.,hyperlipoproteinemia type Ia, hyperlipoproteinemia type Ib,hyperlipoproteinemia type Ic, hyperlipoproteinemia type IIa,hyperlipoproteinemia type IIb, hyperlipoproteinemia type III,hyperlipoproteinemia type IV, and hyperlipoproteinemia type V.

In another embodiment, a cardiovascular disease comprises a coronaryheart disease. A coronary heart disease refers to a conditioncharacterized by failure of the coronary circulation to supply adequateblood flow to cardiac muscle and surrounding tissue. Typically caused bythe narrowing or blockage of the coronary artery, such as, e.g., anatherosclerotic coronary artery disease, a coronary vasospasm, and/or acoronary stenosis. Chest pain and myocardial infarction are commonsymptoms of and conditions caused by coronary heart disease.

In another embodiment, a cardiovascular disease comprises a vascularocclusive disease (VOD). A VOD refers to a condition characterized by anobstruction of a blood vessel. A VOD includes, without limitation, anatherosclerosis, a peripheral vascular disease, and a stenosis.

In an aspect of this embodiment, a VOD comprises an atherosclerosis. Anatherosclerosis refers to a condition characterized by a buildup ofcholesterol and fatty deposits (called plaques) on the inner walls ofthe arteries. These plaques can restrict blood flow to the heart muscleby physically clogging the artery or by causing abnormal artery tone andfunction. Rupture of atherosclerotic plaque is the most common cause ofan ischemia.

In an aspect of this embodiment, a VOD comprises a peripheral vasculardisease (PVD). Peripheral vascular disease (PVD), also known asperipheral arterial disease (PAD) or peripheral artery occlusive disease(PAOD), refers to a condition characterized by an obstruction of largearteries not within the coronary, aortic arch vasculature, or brain. PVDcan result from atherosclerosis, an inflammatory processes leading tostenosis, an embolism, or thrombus formation. It causes either acute orchronic ischemia. PVD also includes a subset of diseases classified asmicrovascular diseases resulting from episodic narrowing of thearteries, such as, e.g., Raynaud's phenomenon, or widening of thearteries, such as, e.g., a vascular spasm. Symptoms of PVD include,without limitation, pain, weakness, numbness, or cramping in muscles dueto decreased blood flow, sores, wounds, or ulcers that heal slowly ornot at all, blueness or paleness in limb, coolness in limb, diminishedhair and nail growth on affected limb and digits. About 20% of patientswith mild PAD may be asymptomatic.

In another embodiment, a cardiovascular disease comprises acardiomyopathy. A cardiomyopathy refers to a condition characterized bythe deterioration of myocardium function. Symptoms and signs may mimicthose of almost any form of heart disease and include chest pain and EKGabnormalities. A mild cardiomyopathy is frequently asymptomatic. A moresevere case is associated with heart failure, arrhythmias, systemicembolization and/or sudden cardiac death. A cardiomyopathy may beclassified functionally, as involving dilation, hypertrophy, orrestriction.

A cardiomyopathy may also be classified as either extrinsic orintrinsic. An extrinsic cardiomyopathy refers to a cardiomyopathy wherethe primary pathology is outside the myocardium itself. For example, anextrinsic cardiomyopathy may be caused by a metabolic/storage disorder,an endocrine disorder, a neuromuscular disorder, a nutritional disorder,an inflammation, a toxicity (including drug and alcohol), an ischemia,and/or an infection (including Hepatitis C). Non-limiting examples ofextrinsic cardiomyopathies include acromegaly, alcoholic cardiomyopathy,amyloidosis, Chagas disease, chemotherapy, diabetic cardiomyopathy,hemochromatosis, hypertensive cardiomyopathy, hyperthyroidism,inflammatory cardiomyopathy, ischemic cardiomyopathy, musculardystrophy, valvular cardiomyopathy, a cardiomyopathy secondary to asystemic metabolic disease, a cardiomyopathy secondary to a systemicnutritional disease, a coronary artery disease, and a congenital heartdisease.

An intrinsic cardiomyopathy refers to a cardiomyopathy where there is aweakness in the muscle of the heart that is not due to an identifiableexternal cause, i.e., of unknown origin. Intrinsic cardiomyopathiescomprise a variety of disease states due to its idiopathic nature andmay be classified as genetic, mixed or acquired. Non-limiting examplesof intrinsic cardiomyopathies include dilated cardiomyopathy (DCM),hypertrophic cardiomyopathy (HCM or HOCM), arrhythmogenic rightventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM),noncompaction cardiomyopathy, isolated ventricular non-compaction,mitochondrial myopathy, Takotsubo cardiomyopathy, and Loefflerendocarditis.

In another embodiment, a cardiovascular disease comprises a vasculitis.Vasculitis is a varied group of disorders featuring inflammation of avessel wall including lymphatic vessels and blood vessels like veins(phlebitis), arteries (arteritis) and capillaries due to leukocytemigration and resultant damage. The inflammation may affect any sizeblood vessel, anywhere in the body. It may affect either arteries and/orveins. The inflammation may be focal, meaning that it affects a singlelocation within a vessel; or it may be widespread, with areas ofinflammation scattered throughout a particular organ or tissue, or evenaffecting more than one organ system in the body. Vasculitis include,without limitation, Buerger's disease (thromboangiitis obliterans),cerebral vasculitis (central nervous system vasculitis), Churg-Straussarteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis,giant cell (temporal) arteritis, Golfer's vasculitis, Henoch-Schonleinpurpura, hypersensitivity vasculitis (allergic vasculitis), Kawasakidisease, microscopic polyarteritis/polyangiitis, polyarteritis nodosa,polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu arteritis,thrombophlebitis, Wegener's granulomatosis, and vasculitis secondary toconnective tissue disorders like systemic lupus erythematosus (SLE),rheumatoid arthritis (RA), relapsing polychondritis, Behçet's disease,or other connective tissue disorders, vasculitis secondary to viralinfection.

In another embodiment, a cardiovascular disease comprises aninflammatory heart disease. An inflammatory heart disease refers to acondition characterized by inflammation of the heart muscle and/or thetissue surrounding it. Non-limiting examples of inflammatory heartdisease include endocarditis, inflammatory cardiomegaly, andmyocarditis.

In another embodiment, a cardiovascular disease comprises an ischemicheart disease. Ischemic heart disease, or myocardial ischemia, refers toa condition characterized by reduced blood supply of the heart muscle,usually due to a narrowing or blockage of a coronary artery. Symptoms ofischemic heart disease include chest pain on exertion, in cold weatheror emotional situations, acute chest pain, acute coronary syndrome,unstable angina, myocardial infarction, heart failure, difficulty inbreathing or swelling of the extremities.

In another embodiment, a cardiovascular disease comprises a congestiveheart failure. A congestive heart failure, or congestive cardiacfailure, refers to a condition characterized by a heart abnormality thatcannot result from any structural or functional cardiac disorder thatimpairs the ability of the heart to fill with or pump a sufficientamount of blood throughout the body.

In another embodiment, a cardiovascular disease comprises a hypertensiveheart disease. A hypertensive heart disease refers to a conditioncharacterized by high blood pressure, especially localized high bloodpressure. Conditions that can be caused by hypertensive heart diseaseinclude, without limitation, left ventricular hypertrophy, coronaryheart disease, congestive heart failure, hypertensive cardiomyopathy,and cardiac arrhythmias.

In another embodiment, a cardiovascular disease comprises a valvularheart disease. A valvular heart disease refers to a conditioncharacterized by a malfunction of one or more valves of the heart. Majorheart valves which may be affected by valvular heart disease, including,without limitation, tricuspid valve, right aortic valve, mitral valve,and left aortic valve.

A composition or compound is administered to an individual. Anindividual is typically a human being. Typically, any individual who isa candidate for a conventional cardiovascular disease treatment is acandidate for a cardiovascular disease treatment disclosed herein.Pre-operative evaluation typically includes routine history and physicalexamination in addition to thorough informed consent disclosing allrelevant risks and benefits of the procedure.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in a therapeutically effective amount. As used herein, the term“effective amount” is synonymous with “therapeutically effectiveamount”, “effective dose”, or “therapeutically effective dose” and whenused in reference to treating a cardiovascular disease refers to theminimum dose of a therapeutic compound disclosed herein necessary toachieve the desired therapeutic effect and includes a dose sufficient toreduce a symptom associated with a cardiovascular disease. Theeffectiveness of a therapeutic compound disclosed herein in treating acardiovascular disease is determined by observing an improvement in anindividual based upon one or more clinical symptoms, and/orphysiological indicators associated with the condition. An improvementin a cardiovascular disease also can be indicated by a reduced need fora concurrent therapy.

The appropriate effective amount of a therapeutic compound disclosedherein to be administered to an individual for a particularcardiovascular disease can be determined by a person of ordinary skillin the art by taking into account factors, including, withoutlimitation, the type of cardiovascular disease, the location of thecardiovascular disease, the cause of the cardiovascular disease, theseverity of the cardiovascular disease, the degree of relief desired,the duration of relief desired, the particular therapeutic compoundused, the rate of excretion of the therapeutic compound used, thepharmacodynamics of the therapeutic compound used, the nature of theother compounds to be included in the composition, the particular routeof administration, the particular characteristics, history and riskfactors of the patient, such as, e.g., age, weight, general health andthe like, or any combination thereof. Additionally, where repeatedadministration of a therapeutic compound is used, an effective amount ofa therapeutic compound will further depend upon factors, including,without limitation, the frequency of administration, the half-life ofthe therapeutic compound, or any combination thereof. In is known by aperson of ordinary skill in the art that an effective amount of atherapeutic compound disclosed herein can be extrapolated from in vitroassays and in vivo administration studies using animal models prior toadministration to humans.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein reduces a symptom associated witha cardiovascular disease by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95% or at least 100%. In other aspects of this embodiment, atherapeutically effective amount of a therapeutic compound disclosedherein reduces a symptom associated with a cardiovascular disease by,e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%,at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, atmost 90%, at most 95% or at most 100%. In yet other aspects of thisembodiment, a therapeutically effective amount of a therapeutic compounddisclosed herein reduces a symptom associated with a cardiovasculardisease by, e.g., about 10% to about 100%, about 10% to about 90%, about10% to about 80%, about 10% to about 70%, about 10% to about 60%, about10% to about 50%, about 10% to about 40%, about 20% to about 100%, about20% to about 90%, about 20% to about 80%, about 20% to about 20%, about20% to about 60%, about 20% to about 50%, about 20% to about 40%, about30% to about 100%, about 30% to about 90%, about 30% to about 80%, about30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

In yet other aspects of this embodiment, a therapeutically effectiveamount of a therapeutic compound disclosed herein generally is in therange of about 0.001 mg/kg/day to about 100 mg/kg/day. In aspects ofthis embodiment, an effective amount of a therapeutic compound disclosedherein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day,at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day,at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, atleast 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, atleast 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. Inother aspects of this embodiment, an effective amount of a therapeuticcompound disclosed herein may be in the range of, e.g., about 0.001mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100mg/kg/day. In yet other aspects of this embodiment, an effective amountof a therapeutic compound disclosed herein may be in the range of, e.g.,about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day toabout 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100mg/kg/day. In still other aspects of this embodiment, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/dayto about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be in the range of, e.g.,about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 5 mg/kg/day to about 10mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day toabout 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day toabout 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100mg/kg/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa cardiovascular disease may comprise a one-time administration of aneffective dose of a pharmaceutical composition disclosed herein.Alternatively, treatment of a cardiovascular disease may comprisemultiple administrations of an effective dose of a pharmaceuticalcomposition carried out over a range of time periods, such as, e.g.,once daily, twice daily, trice daily, once every few days, or onceweekly. The timing of administration can vary from individual toindividual, depending upon such factors as the severity of anindividual's symptoms. For example, an effective dose of apharmaceutical composition disclosed herein can be administered to anindividual once daily for an indefinite period of time, or until theindividual no longer requires therapy. A person of ordinary skill in theart will recognize that the condition of the individual can be monitoredthroughout the course of treatment and that the effective amount of apharmaceutical composition disclosed herein that is administered can beadjusted accordingly.

In one embodiment, upon administration to an individual, apharmaceutical composition comprising a therapeutic compound disclosedherein results in a bio-distribution of the therapeutic compounddifferent than a bio-distribution of the therapeutic compound includedin the same pharmaceutical composition, except without an adjuvantdisclosed herein.

In another embodiment, upon administration to an individual, atherapeutic compound of the pharmaceutical composition disclosed hereinis delivered to a macrophage. Macrophages are one of the key cell typesbelieved to be involved in the control of the inflammation response. Theresultant high level of a therapeutic compound having an activity thatnormalizes lipid levels and/or anti-inflammatory activity present in themacrophages results in a clinically effective treatment ofcardiovascular disease. In an aspect of this embodiment, uponadministration to an individual, a therapeutically effective amount of atherapeutic compound of the pharmaceutical composition disclosed hereinis preferentially delivered to a macrophage. In other aspect of thisembodiment, upon administration to an individual, a therapeutic compoundof the pharmaceutical composition disclosed herein is substantiallydelivered to a macrophage. In yet other aspect of this embodiment, uponadministration to an individual, the amount of a therapeutic compound ofthe pharmaceutical composition disclosed herein delivered to amacrophage is, e.g., at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or at least 100% of the total amount of the therapeutic compoundcontained in the administered pharmaceutical composition. In still otheraspects of this embodiment, upon administration to an individual, theamount of a therapeutic compound of the pharmaceutical compositiondisclosed herein delivered to a macrophage is in a range of, e.g., about5% to about 100%, about 10% to about 100%, about 15% to about 100%,about 20% to about 100%, about 25% to about 100%, about 30% to about100%, about 35% to about 100%, about 40% to about 100%, about 45% toabout 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% toabout 90%, about 30% to about 90%, about 35% to about 90%, about 40% toabout 90%, about 45% to about 90%, about 50% to about 90%, about 5% toabout 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% toabout 80%, about 40% to about 80%, about 45% to about 80%, about 50% toabout 80%, about 5% to about 70%, about 10% to about 70%, about 15% toabout 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 70%, about 35% to about 70%, about 40% to about 70%, about 45% toabout 70%, or about 50% to about 70% of the total amount of thetherapeutic compound contained in the administered pharmaceuticalcomposition.

In another embodiment, upon administration to an individual, apharmaceutical composition disclosed herein reduces gastric irritation.In an aspect of this embodiment, a pharmaceutical composition disclosedherein substantially reduces gastric irritation. In yet anotherembodiment, upon administration to an individual, a pharmaceuticalcomposition disclosed herein reduces gastric irritation when compared tothe same pharmaceutical composition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In an aspect of this embodiment, apharmaceutical composition disclosed herein substantially reducesgastric irritation when compared to the same pharmaceutical compositiondisclosed herein, except without the pharmaceutically-acceptableadjuvant. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein reduces gastric irritation by, e.g., atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, or at least 100%.In yet other aspects of this embodiment, a pharmaceutical compositiondisclosed herein reduces gastric irritation in a range of, e.g., about5% to about 100%, about 10% to about 100%, about 15% to about 100%,about 20% to about 100%, about 25% to about 100%, about 30% to about100%, about 35% to about 100%, about 40% to about 100%, about 45% toabout 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% toabout 90%, about 30% to about 90%, about 35% to about 90%, about 40% toabout 90%, about 45% to about 90%, about 50% to about 90%, about 5% toabout 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% toabout 80%, about 40% to about 80%, about 45% to about 80%, about 50% toabout 80%, about 5% to about 70%, about 10% to about 70%, about 15% toabout 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 70%, about 35% to about 70%, about 40% to about 70%, about 45% toabout 70%, or about 50% to about 70%.

In another embodiment, upon administration to an individual, apharmaceutical composition disclosed herein reduces intestinalirritation. In an aspect of this embodiment, a pharmaceuticalcomposition disclosed herein substantially reduces intestinalirritation. In yet another embodiment, upon administration to anindividual, a pharmaceutical composition disclosed herein reducesintestinal irritation when compared to the same pharmaceuticalcomposition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In an aspect of this embodiment, apharmaceutical composition disclosed herein substantially reducesintestinal irritation when compared to the same pharmaceuticalcomposition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In other aspects of thisembodiment, a pharmaceutical composition disclosed herein reducesintestinal irritation by, e.g., at least 5%, at least 10%, at least 20%,at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, or at least 100% when compared to the samepharmaceutical composition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In yet other aspects of thisembodiment, a pharmaceutical composition disclosed herein reducesintestinal irritation by, e.g., about 5% to about 100%, about 10% toabout 100%, about 15% to about 100%, about 20% to about 100%, about 25%to about 100%, about 30% to about 100%, about 35% to about 100%, about40% to about 100%, about 45% to about 100%, about 50% to about 100%,about 5% to about 90%, about 10% to about 90%, about 15% to about 90%,about 20% to about 90%, about 25% to about 90%, about 30% to about 90%,about 35% to about 90%, about 40% to about 90%, about 45% to about 90%,about 50% to about 90%, about 5% to about 80%, about 10% to about 80%,about 15% to about 80%, about 20% to about 80%, about 25% to about 80%,about 30% to about 80%, about 35% to about 80%, about 40% to about 80%,about 45% to about 80%, about 50% to about 80%, about 5% to about 70%,about 10% to about 70%, about 15% to about 70%, about 20% to about 70%,about 25% to about 70%, about 30% to about 70%, about 35% to about 70%,about 40% to about 70%, about 45% to about 70%, or about 50% to about70% when compared to the same pharmaceutical composition disclosedherein, except without the pharmaceutically-acceptable adjuvant.

A pharmaceutical composition disclosed herein can also be administeredto an individual in combination with other therapeutic compounds toincrease the overall therapeutic effect of the treatment. The use ofmultiple compounds to treat an indication can increase the beneficialeffects while reducing the presence of side effects.

Aspects of the present invention can also be described as follows:

-   1. A pharmaceutical composition comprising: a) a therapeutic    compound, wherein the therapeutic compound has an activity that    normalizes lipid levels; and b) a pharmaceutically-acceptable    adjuvant.-   2. The pharmaceutical composition according to embodiment 1, wherein    the composition further comprises a pharmaceutically-acceptable    solvent.-   3. A pharmaceutical composition comprising: a) a therapeutic    compound, wherein the therapeutic compound has an activity that    normalizes lipid levels; b) a pharmaceutically-acceptable solvent;    and c) a pharmaceutically-acceptable adjuvant.-   4. A pharmaceutical composition comprising: a) a therapeutic    compound, wherein the therapeutic compound has an activity that    normalizes lipid levels; b) a pharmaceutically-acceptable solvent;    and c) a pharmaceutically-acceptable adjuvant, wherein the ratio of    the pharmaceutically-acceptable solvent to    pharmaceutically-acceptable adjuvant is in a range from about 0:1 to    about 1:25.-   5. The pharmaceutical composition according to embodiment 2 or 3,    wherein the ratio of the pharmaceutically-acceptable solvent to    pharmaceutically-acceptable adjuvant is in a range from about 0:1 to    about 1:25.-   6. The pharmaceutical composition according to embodiments 1-5,    wherein the activity that normalizes lipid levels has an    anti-hyperlipidemia activity.-   7. The pharmaceutical composition according to embodiment 6, wherein    the anti-hyperlipidemia activity reduces the levels of VLDL, IDL,    LDL, or a combination thereof by at least 10%.-   8. The pharmaceutical composition according to embodiment 7, wherein    the anti-hyperlipidemia activity increases the level of HDL by,    e.g., at least 2%-   9. The pharmaceutical composition according to embodiments 1-8,    wherein the activity that normalizes lipid levels reduces the level    of an inflammation inducing prostaglandin.-   10. The pharmaceutical composition according to embodiment 9,    wherein the level of the inflammation inducing prostaglandin is    reduced by at least 10%.-   11. The pharmaceutical composition according to embodiments 1-10,    wherein the activity that normalizes lipid levels stimulates a PPAR    signaling pathway.-   12. The pharmaceutical composition according to embodiment 11,    wherein the PPAR signaling pathway is stimulated by at least 10%.-   13. The pharmaceutical composition according to embodiments 1-12,    wherein the activity that normalizes lipid levels induces apoptosis    of Macrophage M1 cells, promotes differentiation of Macrophage M2    cells, or both.-   14. The pharmaceutical composition according to embodiments 1-13,    wherein the activity that normalizes lipid levels reduces the levels    of Interferon-gamma (IFNγ), Tumor necrosis factor-alpha (TNF-α),    Interleukin-12 (IL-12), or a combination thereof released from Th1    cells, increases the levels of IL-10 released from a Th2 cell, or    both.-   15. The pharmaceutical composition according to embodiment 14,    wherein the levels of IFNγ, TNF-α, IL-12, or a combination thereof    released from a Th1 cell are reduced by at least 10%.-   16. The pharmaceutical composition according to embodiment 14,    wherein the levels of IL-10 released from a Th2 cell are increased    by at least 10%.-   17. The pharmaceutical composition according to embodiments 1-16,    wherein the activity that normalizes lipid levels reduces the level    of an inflammation inducing molecule.-   18. The pharmaceutical composition according to embodiment 17,    wherein the inflammation inducing molecule comprises substance P    (SP), calcitonin gene-related peptide (CGRP), glutamate, or a    combination thereof.-   19. The pharmaceutical composition according to embodiments 1-18,    wherein the therapeutic compound has a log P value indicating that    the compound is soluble in an organic solvent.-   20. The pharmaceutical composition according to embodiments 1-19,    wherein the therapeutic compound has a log P value of more than 1.0.-   21. The pharmaceutical composition according to embodiments 1-19,    wherein the therapeutic compound has a log P value of more than 2.0.-   22. The pharmaceutical composition according to embodiments 1-21,    wherein the therapeutic compound has a polar surface area that is    hydrophobic.-   23. The pharmaceutical composition according to embodiments 1-22,    wherein the therapeutic compound has a polar surface area that is    less than 8.0 nm².-   24. The pharmaceutical composition according to embodiments 1-22,    wherein the therapeutic compound has a polar surface area that is    less than 6.0 nm².-   25. The pharmaceutical composition according to embodiments 1-24,    wherein the therapeutic compound comprises a non-steroidal    anti-inflammatory drug (NSAID).-   26. The pharmaceutical composition according to embodiment 25,    wherein the NSAID comprises a salicylate derivative NSAID, a p-amino    phenol derivative NSAID, a propionic acid derivative NSAID, an    acetic acid derivative NSAID, an enolic acid derivative NSAID, a    fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX)    inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a    selective cyclooxygenase 2 (COX 2) inhibitor or a combination    thereof.-   27. The pharmaceutical composition according to embodiments 1-26,    wherein the therapeutic compound comprises a PPARγ agonist.-   28. The pharmaceutical composition according to embodiment 27,    wherein the PPARγ agonist comprises Monascin, Irbesartan,    Telmisartan, mycophenolic acid, Resveratrol,    Delta(9)-tetrahydrocannabinol, a cannabidiol, Curcumin, Cilostazol,    Benzbromarone, 6-shogaol, glycyrrhetinic acid, a thiazolidinedione,    a NSAID, a fibrate, or a combination thereof.-   29. The pharmaceutical composition according to embodiments 1-28,    wherein the therapeutic compound comprises a nuclear receptor    binding agent.-   30. The pharmaceutical composition according to embodiment 29,    wherein the nuclear receptor binding agent comprises a Retinoic Acid    Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding    agent, a Liver X Receptor (LXR) binding agent, a Vitamin D binding    agent, or a combination thereof.-   31. The pharmaceutical composition according to embodiments 1-30,    wherein the therapeutic compound comprises an anti-hyperlipidemic    agent.-   32. The pharmaceutical composition according to embodiment 31,    wherein the anti-hyperlipidemic agent comprises a fibrate, a statin,    a tocotrienol, a niacin, a bile acid sequestrants (resin), a    cholesterol absorption inhibitor, a pancreatic lipase inhibitor, a    sympathomimetic amine, or a combination thereof.-   33. The pharmaceutical composition according to embodiment 31,    wherein the fibrate comprises-   Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or    a combination thereof.-   34. The pharmaceutical composition according to embodiment 31,    wherein the statin comprises-   Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin,    Rosuvastatin, Simvastatin, or a combination thereof.-   35. The pharmaceutical composition according to embodiment 31,    wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin    B3, or a combination thereof.-   36. The pharmaceutical composition according to embodiment 31,    wherein the bile acid sequestrant comprises Cholestyramine,    Colesevelam, Colestipol, or a combination thereof.-   37. The pharmaceutical composition according to embodiment 31,    wherein the cholesterol absorption inhibitor comprises Ezetimibe, a    phytosterol, a sterol, a stanol, or a combination thereof.-   38. The pharmaceutical composition according to embodiment 31,    wherein the fat absorption inhibitor comprises Orlistat-   39. The pharmaceutical composition according to embodiment 31,    wherein the sympathomimetic amine comprises Clenbuterol, Salbutamol,    ephedrine, pseudoephedrine, methamphetamine, amphetamine,    phenylephrine, isoproterenol, dobutamine, methylphenidate,    lisdexamfetamine, cathine, cathinone, methcathinone, cocaine,    benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV),    4-methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a    combination thereof.-   40. The pharmaceutical composition according to embodiments 1-39,    wherein the therapeutic compound comprises an ester of a therapeutic    compound.-   41. The pharmaceutical composition according to embodiments 1-40,    wherein the therapeutic compound comprises an ester of a therapeutic    compound according to embodiments 25-39.-   42. The pharmaceutical composition according to embodiments 1-41,    wherein the pharmaceutically-acceptable solvent is less than about    20% (v/v).-   43. The pharmaceutical composition according to embodiments 1-42,    wherein the pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable polar aprotic solvent, a    pharmaceutically-acceptable polar protic solvent, a    pharmaceutically-acceptable non-polar solvent, or a combination    thereof.-   44. The pharmaceutical composition according to embodiments 1-43,    wherein the pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable alcohol.-   45. The pharmaceutical composition according to embodiment 44,    wherein the pharmaceutically-acceptable alcohol comprises an acyclic    alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated    aliphatic alcohol, an alicyclic alcohol, or a combination thereof.-   46. The pharmaceutical composition according to embodiment 44,    wherein the pharmaceutically-acceptable alcohol comprises a C₁₋₂₀    alcohol.-   47. The pharmaceutical composition according to embodiment 44,    wherein the pharmaceutically-acceptable alcohol comprises methanol,    ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a    combination thereof.-   48. The pharmaceutical composition according to embodiments 1-47,    wherein the pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable ester of pharmaceutically-acceptable    alcohol and an acid.-   49. The pharmaceutical composition according to embodiment 48,    wherein the pharmaceutically-acceptable ester comprises methyl    acetate, methyl buterate, methyl formate, ethyl acetate, ethyl    buterate, ethyl formate, propyl acetate, propyl buterate, propyl    formate, butyl acetate, butyl buterate, butyl formate, isobutyl    acetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentyl    buterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl    buterate, and 1-hexadecyl formate, or a combination thereof.-   50. The pharmaceutical composition according to embodiments 1-49,    wherein the pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable polyethylene glycol (PEG) polymer.-   51. The pharmaceutical composition according to embodiment 50,    wherein the pharmaceutically-acceptable polyethylene glycol (PEG)    polymer is less than about 2,000 g/mol.-   52. The pharmaceutical composition according to embodiment 50,    wherein the pharmaceutically-acceptable polyethylene glycol (PEG)    polymer is more than about 2,000 g/mol.-   53. The pharmaceutical composition according to embodiments 1-52,    wherein the pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable glyceride.-   54. The pharmaceutical composition according to embodiment 53,    wherein the pharmaceutically-acceptable glyceride comprises a    monoglyceride, a diglyceride, a triglyceride, an acetylated    monoglyceride, an acetylated diglyceride, an acetylated    triglyceride, or a combination thereof.-   55. The pharmaceutical composition according to embodiments 1-54,    wherein the pharmaceutically-acceptable solvent is a liquid at 20°    C.-   56. The pharmaceutical composition according to embodiments 1-54,    wherein the pharmaceutically-acceptable solvent is a solid at 20° C.-   57. The pharmaceutical composition according to embodiment 56,    wherein the pharmaceutically-acceptable solid solvent comprises    menthol.-   58. The pharmaceutical composition according to embodiments 1-57,    wherein the adjuvant is at least 80% (v/v).-   59. The pharmaceutical composition according to embodiments 1-58,    wherein the pharmaceutically-acceptable adjuvant is a liquid at 20°    C.-   60. The pharmaceutical composition according to embodiments 1-58,    wherein the pharmaceutically-acceptable adjuvant is a solid at 20°    C.-   61. The pharmaceutical composition according to embodiments 1-60,    wherein the pharmaceutically-acceptable adjuvant comprises a    pharmaceutically-acceptable lipid.-   62. The pharmaceutical composition according to embodiment 61,    wherein the pharmaceutically-acceptable lipid comprises a saturated    fatty acid, an unsaturated fatty acid, or a combination thereof.-   63. The pharmaceutical composition according to embodiment 61 or 62,    wherein the pharmaceutically-acceptable lipid comprises two or more    saturated or unsaturated fatty acids.-   64. The pharmaceutical composition according to embodiment 63,    wherein the two or more saturated or unsaturated fatty acids    includes palmitic acid, stearic acid, oleic acid, linoleic acid,    linolenic acid, or a combination thereof.-   65. The pharmaceutical composition according to embodiments 62-64,    wherein the unsaturated fatty acid has a melting point temperature    of 20° C. or below.-   66. The pharmaceutical composition according to embodiments 62-64,    wherein the unsaturated fatty acid is a solid at 20° C.-   67. The pharmaceutical composition according to embodiments 62-64,    wherein the unsaturated fatty acid comprises an omega fatty acid.-   68. The pharmaceutical composition according to embodiment 61,    wherein the pharmaceutically-acceptable lipid comprises a    pharmaceutically-acceptable oil.-   69. The pharmaceutical composition according to embodiment 68,    wherein the pharmaceutically-acceptable oil comprises almond oil,    arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn    oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed    oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil,    safflower oil, sesame oil, soybean oil, soya oil, sunflower oil,    walnut oil, wheat germ oil, or a combination thereof.-   70. The pharmaceutical composition according to embodiments 1-69,    wherein the pharmaceutical composition further comprises a    pharmaceutically-acceptable stabilizing agent.-   71. The pharmaceutical composition according to embodiment 70,    wherein the pharmaceutically-acceptable stabilizing agent comprises    water, a sacrificial acid comprising a fatty acid component and    acetic acid, ethyl acetate, a sodium acetate/acetic acid, a    monoglyceride, an acetylated monoglyceride, a diglyceride, an    acetylated diglyceride, a fatty acid, a fatty acid salt, or a    combination thereof.-   72. The pharmaceutical composition according to embodiment 70,    wherein the pharmaceutically-acceptable stabilizing agent comprises    a pharmaceutically-acceptable emulsifying agent.-   73. The pharmaceutical composition according to embodiment 72,    wherein the pharmaceutically-acceptable emulsifying agent comprises    a surfactant, a polysaccharide, a lectin, a phospholipid, or a    combination thereof.-   74. The pharmaceutical composition according to embodiments 1-71,    wherein the pharmaceutical composition does not comprise a    pharmaceutically-acceptable emulsifying agent.-   75. A method of preparing a pharmaceutical composition, the method    comprising the step of contacting a therapeutic compound with a    pharmaceutically-acceptable adjuvant under conditions which allow    the formation of the pharmaceutical composition.-   76. A method of preparing a pharmaceutical composition, the method    comprising the steps: a) contacting a pharmaceutically-acceptable    solvent with a therapeutic compound under conditions which allow the    therapeutic compound to dissolve in the pharmaceutically-acceptable    solvent, thereby forming a solution, wherein the therapeutic    compound has anti-inflammatory activity, and b) contacting the    solution formed in step (a) with a pharmaceutically-acceptable    adjuvant under conditions which allow the formation of the    pharmaceutical composition.-   77. A method of preparing a pharmaceutical composition, the method    comprising the steps: a) contacting a pharmaceutically-acceptable    solvent with a therapeutic compound under conditions which allow the    therapeutic compound to dissolve in the pharmaceutically-acceptable    solvent, thereby forming a solution, wherein the therapeutic    compound has anti-inflammatory activity, and b) contacting the    solution formed in step (a) with a pharmaceutically-acceptable    adjuvant under conditions which allow the formation of the    pharmaceutical composition, wherein the ratio of the    pharmaceutically-acceptable solvent to pharmaceutically-acceptable    adjuvant is in a range from about 0:1 to about 1:25.-   78. The method according to embodiments 75-77, wherein the    therapeutic compound has a log P value indicating that the compound    is soluble in an organic solvent.-   79. The method according to embodiment 75-78, wherein the    therapeutic compound has a log P value of more than 1.0.-   80. The method according to embodiment 75-78, wherein the    therapeutic compound has a log P value of more than 2.0.-   81. The method according to embodiments 75-80, wherein the    therapeutic compound has a polar surface area that is hydrophobic.-   82. The method according to embodiments 75-81, wherein the    therapeutic compound has a polar surface area that is less than 8.0    nm².-   83. The method according to embodiments 75-81, wherein the    therapeutic compound has a polar surface area that is less than 6.0    nm².-   84. The method according to embodiments 75-83, wherein the    therapeutic compound comprises a non-steroidal anti-inflammatory    drug (NSAID).-   85. The method according to embodiment 84, wherein the NSAID    comprises a salicylate derivative NSAID, a p-amino phenol derivative    NSAID, a propionic acid derivative NSAID, an acetic acid derivative    NSAID, an enolic acid derivative NSAID, a fenamic acid derivative    NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective    cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2    (COX 2) inhibitor, or a combination thereof.-   86. The method according to embodiments 75-85, wherein the    therapeutic compound comprises a PPARγ agonist.-   87. The method according to embodiment 86, wherein the PPARγ agonist    comprises Monascin, Irbesartan, Telmisartan, mycophenolic acid,    Resveratrol, Delta(9)-tetrahydrocannabinol, a cannabidiol, Curcumin,    Cilostazol, Benzbromarone, 6-shogaol, glycyrrhetinic acid, a    thiazolidinedione, a NSAID, a fibrate, or a combination thereof.-   88. The method according to embodiments 75-87, wherein the    therapeutic compound comprises a nuclear receptor binding agent.-   89. The method according to embodiment 88, wherein the nuclear    receptor binding agent comprises a-   Retinoic Acid Receptor (RAR) binding agent, a Retinoid X Receptor    (RXR) binding agent, a Liver X Receptor (LXR) binding agent, a    Vitamin D binding agent, or a combination thereof. 90. The method    according to embodiments 75-89, wherein the therapeutic compound    comprises an anti-hyperlipidemic agent.-   91. The method according to embodiment 90, wherein the    anti-hyperlipidemic agent comprises a fibrate, a statin, a    tocotrienol, a niacin, a bile acid sequestrants (resin), a    cholesterol absorption inhibitor, a pancreatic lipase inhibitor, a    sympathomimetic amine, or a combination thereof.-   92. The method according to embodiment 91, wherein the fibrate    comprises Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil,    Fenofibrate, or a combination thereof.-   93. The method according to embodiment 91, wherein the statin    comprises Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin,    Pravastatin, Rosuvastatin, Simvastatin, or a combination thereof.-   94. The method according to embodiment 91, wherein the niacin    comprises acipimox, niacin, nicotinamide, vitamin B3, or a    combination thereof.-   95. The method according to embodiment 91, wherein the bile acid    sequestrant comprises Cholestyramine, Colesevelam, Colestipol, or a    combination thereof.-   96. The method according to embodiment 91, wherein the cholesterol    absorption inhibitor comprises Ezetimibe, a phytosterol, a sterol, a    stanol, or a combination thereof.-   97. The method according to embodiment 91, wherein the fat    absorption inhibitor comprises Orlistat-   98. The method according to embodiment 91, wherein the    sympathomimetic amine comprises Clenbuterol, Salbutamol, ephedrine,    pseudoephedrine, methamphetamine, amphetamine, phenylephrine,    isoproterenol, dobutamine, methylphenidate, lisdexamfetamine,    cathine, cathinone, methcathinone, cocaine, benzylpiperazine (BZP),    methylenedioxypyrovalerone (MDPV), 4-methylaminorex, pemoline,    phenmetrazine, propylhexedrine, or a combination thereof.-   99. The method according to embodiments 75-98, wherein the    therapeutic compound comprises an ester of a therapeutic compound.-   100. The method according to embodiments 75-99, wherein the    therapeutic compound comprises an ester of a therapeutic compound    according to embodiments 78-99.-   101. The method according to embodiments 76-100, wherein the    pharmaceutically-acceptable solvent is less than about 20% (v/v).-   102. The method according to embodiments 76-101, wherein the    pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable polar aprotic solvent, a    pharmaceutically-acceptable polar protic solvent, a    pharmaceutically-acceptable non-polar solvent, or a combination    thereof.-   103. The method according to embodiments 76-102, wherein the    pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable alcohol.-   104. The method according to embodiment 103, wherein the    pharmaceutically-acceptable alcohol comprises an acyclic alcohol, a    monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic    alcohol, an alicyclic alcohol, or a combination thereof.-   105. The method according to embodiment 103, wherein the    pharmaceutically-acceptable alcohol comprises a C₁₋₂₀ alcohol.-   106. The method according to embodiment 103, wherein the    pharmaceutically-acceptable alcohol comprises methanol, ethanol,    propanol, butanol, pentanol, 1-hexadecanol, or a combination    thereof.-   107. The method according to embodiment 103, wherein the    pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable ester of pharmaceutically-acceptable    alcohol and an acid.-   108. The method according to embodiment 107, wherein the    pharmaceutically-acceptable ester comprises methyl acetate, methyl    buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl    formate, propyl acetate, propyl buterate, propyl formate, butyl    acetate, butyl buterate, butyl formate, isobutyl acetate, isobutyl    buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl    formate, and 1-hexadecyl acetate, 1-hexadecyl buterate, and    1-hexadecyl formate, or a combination thereof.-   109. The method according to embodiments 76-108, wherein the    pharmaceutically-acceptable solvent is a pharmaceutically-acceptable    polyethylene glycol (PEG) polymer.-   110. The method according to embodiment 109, wherein the    pharmaceutically-acceptable polyethylene glycol (PEG) polymer is    less than about 2,000 g/mol.-   111. The method according to embodiment 109, wherein the    pharmaceutically-acceptable polyethylene glycol (PEG) polymer is    more than about 2,000 g/mol.-   112. The method according to embodiments 76-111, wherein the    pharmaceutically-acceptable solvent comprises a    pharmaceutically-acceptable glyceride.-   113. The method according to embodiments 112, wherein the    pharmaceutically-acceptable glyceride is a monoglyceride, a    diglyceride, a triglyceride, an acetylated monoglyceride, an    acetylated diglyceride, an acetylated triglyceride, or a combination    thereof.-   114. The method according to embodiments 76-113, wherein the    pharmaceutically-acceptable solvent is a liquid at 20° C.-   115. The method according to embodiments 76-113, wherein the    pharmaceutically-acceptable solvent is a solid at 20° C.-   116. The method according to embodiment 113, wherein the    pharmaceutically-acceptable solid solvent is menthol.-   117. The method according to embodiments 75-116, wherein the    pharmaceutically-acceptable adjuvant is at least 80% (v/v).-   118. The method according to embodiments 75-117, wherein the    pharmaceutically-acceptable adjuvant is a liquid at 20° C.-   119. The method according to embodiments 75-117, wherein the    pharmaceutically-acceptable adjuvant is a solid at 20° C.-   120. The method according to embodiments 75-119, wherein the    pharmaceutically-acceptable adjuvant comprises a    pharmaceutically-acceptable lipid.-   121. The method according to embodiment 120, wherein the    pharmaceutically-acceptable lipid comprises a    pharmaceutically-acceptable saturated fatty acid, an unsaturated    fatty acid, or a combination thereof.-   122. The method according to embodiment 120 or 121, wherein the    pharmaceutically-acceptable lipid comprises two or more    pharmaceutically-acceptable saturated or unsaturated fatty acids.-   123. The method according to embodiments 122, wherein the two or    more pharmaceutically-acceptable saturated or unsaturated fatty    acids include palmitic acid, stearic acid, oleic acid, linoleic    acid, linolenic acid, or a combination thereof.-   124. The method according to embodiments 121-123, wherein the    pharmaceutically-acceptable unsaturated fatty acid has a melting    point temperature of 20° C. or below.-   125. The method according to embodiments 121-123, wherein the    pharmaceutically-acceptable unsaturated fatty acid is a solid at 20°    C.-   126. The method according to embodiments 121-125, wherein the    pharmaceutically-acceptable unsaturated fatty acid comprises an    omega fatty acid.-   127. The method according to embodiments 120-126, wherein the    pharmaceutically-acceptable lipid comprises a    pharmaceutically-acceptable oil.-   128. The method according to embodiment 127, wherein the    pharmaceutically-acceptable oil comprises almond oil, arachis oil,    avocado oil, canola oil, castor oil, coconut oil, corn oil,    cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil,    olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil,    safflower oil, sesame oil, soybean oil, soya oil, sunflower oil,    walnut oil, wheat germ oil, or a combination thereof.-   129. The method according to embodiments 76 or 78-128, wherein in    step (b) the ratio of the pharmaceutically-acceptable solvent to    pharmaceutically-acceptable adjuvant is in a range from about 0:1 to    about 1:25.-   130. The method according to embodiments 75-129, wherein the    step (a) further comprising contacting a pharmaceutically-acceptable    stabilizing agent with the pharmaceutically-acceptable solvent and    the therapeutic compound.-   131. The method according to embodiment 130, wherein the    pharmaceutically-acceptable stabilizing agent comprises water, a    sacrificial acid comprising a fatty acid component and acetic acid,    ethyl acetate, a sodium acetate/acetic acid, a monoglyceride, an    acetylated monoglyceride, a diglyceride, an acetylated diglyceride,    a fatty acid, a fatty acid salt, or a combination thereof.-   132. The method according to embodiment 130 or 131, wherein the    pharmaceutically-acceptable stabilizing agent comprises a    pharmaceutically-acceptable emulsifying agent.-   133. The method according to embodiment 132, wherein the    pharmaceutically-acceptable emulsifying agent comprises a    surfactant, a polysaccharide, a lectin, a phospholipid, or a    combination thereof.-   134. The method according to embodiments 75-131, wherein the    pharmaceutical composition does not comprise a    pharmaceutically-acceptable emulsifying agent.-   135. The method according to embodiments 76-134, wherein the method    further comprises removing the pharmaceutically-acceptable solvent    from the pharmaceutical composition.-   136. The method according to embodiment 135, wherein at least 5% the    pharmaceutically-acceptable solvent is removed from the    pharmaceutical composition.-   137. The method according to embodiment 135 or 136, wherein at,    removal of solvent from the pharmaceutical composition disclosed    herein is carried out at a temperature of less than 20° C.-   138. The method according to embodiments 75-137, wherein the    pharmaceutical composition made is according to embodiments 1-74.-   139 A method of treating an individual with a cardiovascular    disease, the method comprising the step of: administering to the    individual in need thereof a pharmaceutical composition according to    embodiments 1-74, wherein administration results in a reduction in a    symptom associated with the cardiovascular disease, thereby treating    the individual.-   140. Use of a pharmaceutical composition according to embodiments    1-74 in the manufacture of a medicament for the treatment of a    cardiovascular disease.-   141. Use of a pharmaceutical composition according to embodiments    1-74 for the treatment of a cardiovascular disease.-   142. The method according to embodiment 139 or the use according to    embodiment 140 or 141, wherein the cardiovascular disease is    associated with a hyperlipidemia, a coronary heart disease, an    atherosclerosis, a peripheral vascular disease, a cardiomyopathy, a    vasculitis, an inflammatory heart disease, an ischemic heart    disease, a congestive heart failure, a hypertensive heart disease, a    valvular heart disease, a hypertension, myocardial infarction, a    diabetic cardiac conditions, an aneurysm; an embolism, a dissection,    a pseudoaneurysm, a vascular malformation, a vascular nevus, a    thrombosis, a varicose vein, or a stroke.-   143. The method or use according to embodiment 142, wherein the    hyperlipidemia is dyslipidemia, hypercholesterolemia,    hyperglyceridemia, hypertriglyceridemia, hyperlipoproteinemia, or    hyperchylomicronemia, and combined hyperlipidemia.-   144. The method or use according to embodiment 143, wherein the    hyperlipoproteinemia is hyperlipoproteinemia type Ia,    hyperlipoproteinemia type Ib, hyperlipoproteinemia type Ic,    hyperlipoproteinemia type IIa, hyperlipoproteinemia type IIb,    hyperlipoproteinemia type III, hyperlipoproteinemia type IV, or    hyperlipoproteinemia type V.-   145. The method or use according to embodiment 142, wherein the    vascular occlusive disease (VOD) is an atherosclerosis, a peripheral    vascular disease, or a stenosis.-   146. The method or use according to embodiment 142, wherein the    cardiomyopathy is an extrinsic cardiomyopathy or an intrinsic    cardiomyopathy.-   147. The method or use according to embodiment 146, wherein the    extrinsic cardiomyopathy is acromegaly, alcoholic cardiomyopathy,    amyloidosis, Chagas disease, chemotherapy, diabetic cardiomyopathy,    hemochromatosis, hypertensive cardiomyopathy, hyperthyroidism,    inflammatory cardiomyopathy, ischemic cardiomyopathy, muscular    dystrophy, valvular cardiomyopathy, a cardiomyopathy secondary to a    systemic metabolic disease, a cardiomyopathy secondary to a systemic    nutritional disease, a coronary artery disease, or a congenital    heart disease.-   148. The method or use according to embodiment 146, wherein the    intrinsic cardiomyopathy is dilated cardiomyopathy (DCM),    hypertrophic cardiomyopathy (HCM or HOCM), arrhythmogenic right    ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM),    noncompaction cardiomyopathy, isolated ventricular non-compaction,    mitochondrial myopathy, Takotsubo cardiomyopathy, or Loeffler    endocarditis.-   149. The method or use according to embodiment 142, wherein the    vasculitis is a Buerger's disease, an arteritis, a cerebral    vasculitis, a Churg-Strauss arteritis, a cryoglobulinemia, an    essential cryoglobulinemic vasculitis, a giant cell arteritis, a    Golfer's vasculitis, a Henoch-Schonlein purpura, a hypersensitivity    vasculitis, a Kawasaki disease, a phlebitis, a microscopic    polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia    rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, a    thrombophlebitis, a Wegener's granulomatosis, or a vasculitis    secondary to connective tissue disorder, or vasculitis secondary to    viral infection.-   150. The method or use according to embodiment 149, wherein the    vasculitis secondary to connective tissue disorder is systemic lupus    erythematosus (SLE), rheumatoid arthritis (RA), relapsing    polychondritis, Behçet's disease.-   151. The method or use according to embodiment 142, wherein the    inflammatory heart disease is an endocarditis, an inflammatory    cardiomegaly, or a myocarditis.-   152. The method according to embodiments 139 or 142-151 or the use    according to embodiments 140-151, wherein upon administration to an    individual, the pharmaceutical composition comprising the    therapeutic compound according to embodiments 1-74 results in a    bio-distribution of the therapeutic compound different than a    bio-distribution of the therapeutic compound included in the same    pharmaceutical composition, except without the    pharmaceutically-acceptable adjuvant.-   153. The method according to embodiments 139 or 142-152 or the use    according to embodiments 140-152, wherein upon administration to an    individual, the amount of the therapeutic compound of the    pharmaceutical composition according to embodiments 1-74 delivered    to a macrophage is at least 5% of the total amount of the    therapeutic compound contained in the administered pharmaceutical    composition.-   154. The method according to embodiments 139 or 142-153 or the use    according to embodiments 140-153, wherein upon administration to an    individual, the pharmaceutical composition according to embodiments    1-74 reduces intestinal irritation by at least 5% when compared to    the pharmaceutical composition according to embodiments 1-74, except    without the pharmaceutically-acceptable adjuvant.-   155. The method according to embodiments 139 or 142-154 or the use    according to embodiments 140-154, wherein upon administration to an    individual, the pharmaceutical composition according to embodiments    1-74 reduces gastric irritation by at least 5% when compared to the    pharmaceutical composition according to embodiments 1-74, except    without the pharmaceutically-acceptable adjuvant.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the compounds, alcohols,lipids, pharmaceutical compositions, methods of preparing pharmaceuticalcompositions, or methods or uses of treating a chronic inflammation ordisease associated with chronic inflammation.

Example 1 Liquid Formulations of Pharmaceutical Composition

This example illustrates how to make a pharmaceutical composition asdisclosed herein as a liquid formulation.

Initially, 2,400 mg of ibuprofen was contacted directly with 2.0 mL ofrapeseed oil in an attempt to dissolve a therapeutic compound directlyinto an adjuvant at a concentration of 1,200 mg/mL. However, ibuprofenremained insoluble in the oil and did not dissolve to substantiallymeasurable degree. Ibuprofen remained insolubility even if the mixturewas mixed by vortexing for 20 seconds, the contacting was done at 20° C.or 37° C., and/or the mixture was allowed to incubate for 24 hours at20° C. or 37° C. The insolubility of ibuprofen in rapeseed oil wassurprising given that ibuprofen has a log P value of 3.6; such a highlog P value is indicative of a compound that would readily soluble in anadjuvant like oil.

Since, it was not possible to dissolve ibuprofen directly into oil,despite its high log P value, it was next tried to dissolve atherapeutic drug in a solvent to first create a solution comprising thecompound. As a first step, experiments were conducted to the miscibilityof a solvent in an adjuvant like oil in the absence of a therapeuticcompound. In these experiments 0.5 mL ethanol was contacted with tendifferent volumes of rapeseed oil (Table 1). Each mixture was tested at22° C. and at 37° C. in which the ethanol and oil were initially heatedin a water bath before being mixed together. Mixing was attempted byvortex mixing for 20 seconds, and the containers were allowed to settlebefore visual assessment, either immediately, or after 24 hours. Eachmixture was evaluated to determine whether or not the ethanol andrapeseed oil form immiscible layers, or a homogeneous mixture. Theresults are summarized in Table 1. Mixtures comprising solvent:adjuvantratios of 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6 formed immiscible layers ateither 22° C. or at 37° C., either immediately or after 24 hours ofincubation, indicating that the ethanol and oil did not mix well atthese ratios. However, in solvent:adjuvant ratios above 1:7 ahomogeneous mixture was formed under all conditions tested.

TABLE 1 Liquid Formulations without Therapeutic compound TemperatureComponents 37° C. Solvent Adjuvant 22° C. 24 (mL) (mL) Ratio Immediate24 hours Immediate hours 0.5 0.5 1:1 IL IL IL IL 0.5 1.0 1:2 IL IL IL IL0.5 1.5 1:3 IL IL IL IL 0.5 2.0 1:4 IL IL IL IL 0.5 2.5 1:5 IL IL IL IL0.5 3.0 1:6 IL IL IL IL 0.5 3.5 1:7 HM HM HM HM 0.5 4.0 1:8 HM HM HM HM0.5 4.5 1:9 HM HM HM HM 0.5 5.0  1:10 HM HM HM HM IL, Immiscible layers.HM, Homogeneous mixture.

Once the appropriate ratios of alcohol and lipid necessary to form ahomogenous mixture were determined, it was next determined whethercontacting a therapeutic compound first in a solvent before contactingwith an adjuvant would result in the compound dissolving in thesolvents. To conduct these experiments, either 1,000 mg or 1,200 mg ofibuprofen was dissolved into 0.5 mL of ethanol. The resulting alcoholsolution was then contacted with rapeseed oil at two differentsolvent:adjuvant ratios (1:2 and 1:9). Each mixture was tested at 20° C.and at 37° C. in which the ethanol solution and oil were initiallyheated in a water bath before being mixed together. Mixing was attemptedby vortex mixing for 20 seconds, and the containers were allowed tosettle before visual assessment, either immediately, or after 24 hours.Each mixture was evaluated to determine whether or not the ethanolsolution and rapeseed oil form immiscible layers, or a homogeneousmixture. The results are summarized in Table 2. In contrast to thesituation in the absence of a therapeutic compound, when ibuprofen ispresent in the ethanol, it caused the ethanol and oil to form ahomogeneous mixture under all conditions tested in solvent:adjuvantratios above 1:2. This observation was very surprising because, althoughnot wish to be bound by any theory, it appears that a therapeuticcompound may be having some effect on the manner in which an adjuvantand solvent interact with each other, such that a homogeneous mixture isformed in a way that does not occur when the therapeutic compound isabsent. In addition, the results indicate that a therapeutic compoundcan be formulated at clinically useful concentrations.

TABLE 2 Liquid Formulations with Therapeutic Compound ComponentsTemperature Com- 22° C. 37° C. pound Solvent Adjuvant 24 Imme- 24 (mg)(mL) (mL) Ratio Immediate hours diate hours 500 0.5 1.0 1:2 HM HM HM HM600 0.5 1.0 1:2 HM HM HM HM 500 0.5 4.5 1:9 HM HM HM HM 600 0.5 4.5 1:9HM HM HM HM IL, Immiscible layers. HM, Homogeneous mixture.

Example 2 Liquid Formulations of Pharmaceutical Composition

This example illustrates how to make a pharmaceutical composition asdisclosed herein as a liquid formulation.

To prepare a pharmaceutical composition disclosed herein usinggemfibrozil, the following formulations were examined. In theseexperiments, 600 mg gemfibrozil was contacted with different volumes ofethanol, as the solvent, warmed to 37° C., and the resulting solutionwas then contacted with different volumes of linseed oil, as theadjuvant, warmed to 37° C. (Table 3). Each formulation was evaluated todetermine whether or not the ethanol and linseed oil form immisciblelayers, a clear homogeneous mixture, as well as whether or not thegemfibrozil crystallized out of solution. The results are summarized inTable 3.

Like ibuprofen in Example 1 above, gemfibrozil remained insoluble in theoil alone and did not dissolve to substantially measureable degree. Theformulation comprising 0.2 mL ethanol was unable to completely dissolvegemfibrozil. In addition, although the formulation comprising 0.3 mLethanol was capable of dissolving gemfibrozil, the therapeutic compoundbegan to crystallizing out of solution within 3 hours and completecrystallization occurred within 48 hours. All other formulations testedwere capable of dissolving gemfibrozil and forming a pharmaceuticalcomposition disclosed herein. However, only the formulation comprising0.5 mL ethanol appeared to for a stable pharmaceutical composition inthat gemfibrozil remained completely dissolved after three weeks.

TABLE 3 Liquid Formulations with Therapeutic Compound ComponentsTemperature Compound Solvent Adjuvant 22° C. (mg) (mL) (mL) RatioImmediate 3 weeks 600 0 1.0 — IM N/A 600 0.2 — — IM N/A 600 0.3 0.6 1:2CR CR 600 0.4 0.4 1:1 HM CR 600 0.4 0.8 1:2 HM CR 600 0.5 1.0 1:2 HM HMHM, Clear homogeneous mixture. CR, Crystallization. IM, Immiscible.

Example 3 Liquid Formulations of Pharmaceutical Composition

This example illustrates how to make a pharmaceutical composition asdisclosed herein as a liquid formulation.

To prepare a pharmaceutical composition disclosed herein usingibuprofen, the following formulation was performed. In theseexperiments, 4 g ibuprofen was contacted with 3.6 mL of ethyl acetate,as the solvent, and the resulting solution was then contacted with 76.4mL of rapeseed oil, as the adjuvant. The resulting pharmaceuticalcomposition had a solvent:adjuvant ratio of about 1:21. Thispharmaceutical composition was then placed in a round bottom flask andsubjected to low pressure on a rotary evaporator. The temperature waskept low and evaporation continued to constant weight. The total volumelost was 3.65% of the total weight. The resulting liquid no longerretained the characteristic ethyl acetate odor/taste, indicating thatthere was a substantial removal of ethyl acetate form the pharmaceuticalcomposition.

Example 4 Solid Formulation of Pharmaceutical Composition

This example illustrates how to make a pharmaceutical composition asdisclosed herein as a solid formulation.

Since certain fatty acids are liquid at room temperature, while othersare solid, an examination of the different fatty acids was undertaken inan effort to evaluate the potential of each fatty acid in themanufacture of a solid formulation. This understanding would enable thedevelopment of a wide array of solid formulation by adjusting therelative ratios of each fatty acid. As an initial experiment, linolenicacid, linoleic acid, palmitic acid and stearic acid were evaluated toassess whether it was possible to prepare a pharmaceutical compositiondisclosed herein that could be formulated using only one of these fattyacids to be a solid or semi-solid at 22° C. (simulating room temperatureconditions), but melt into a liquid at 37° C. (simulating internal bodytemperature conditions after ingestion).

Four different test formulations were prepared and evaluated on theirability to form a solid dose formulation at 22° C. and melt into ahomogeneous solution at 37° C. without forming a suspension (Table 4).Formulation 1 was prepared by dissolving 200 mg of Ibuprofen into 400 mgof menthol, and the resulting solution was then mixed with 200 mg ofstearic acid (T_(m) of about 67-72° C.) and heated at 60° C. for 30minutes to form a homogeneous solution. Formulation 1 solidifiedimmediately upon cooling to 22° C. Formulation 1 remained a solid evenafter incubating at 37° C. overnight. Formulation 2 was prepared bydissolving 200 mg of Ibuprofen into 400 mg of menthol, and the resultingsolution was then mixed with 200 mg of palmitic acid (T_(m) of about61-62° C.) and heated at 60° C. for 30 minutes to form a homogeneoussolution. Formulation 2 solidified about 1 hour after cooling to 22° C.Incubating at 37° C. overnight cause Formulation 2 to completely meltinto a clear homogenous liquid. However, Formulation 2 once againsolidified about 1 hour after cooling to 22° C. Formulation 3 wasprepared by dissolving 200 mg of Ibuprofen into 400 mg of menthol, andthe resulting solution was then mixed with 200 mg of linoleic acid(T_(m) of about −5° C.) and heated at 37° C. for 2 hours to form ahomogeneous solution. Formulation 3 remained a liquid, even aftercooling to 22° C. for 72 hours. Formulation 4 was prepared by dissolving200 mg of Ibuprofen into 400 mg of menthol, and the resulting solutionwas then mixed with 200 mg of linolenic acid (T_(m) of about −11° C.)and heated at 37° C. for 2 hours to form a homogeneous solution.Formulation 4 remained a liquid, even after cooling to 22° C. for 72hours.

TABLE 4 Solid Formulations with Therapeutic Compound TemperatureComponents 22° C. 37° C. Compound Solvent Adjuvant Upon 24 72 (mg) (mg)(mg) Ratio Cooling hours hours 200 400 200 (stearic 2:1 Solid Solid —acid) 200 400 200 (palmitic 2:1 Solid Liquid — acid) 200 400 200(linoleic 2:1 Liquid Liquid Liquid acid) 200 400 200 2:1 Liquid LiquidLiquid (linolenic acid)

Based on these data, a solid dosage form of a pharmaceutical compositiondisclosed herein can be made. For example, a pharmaceutical compositionwill be formulated to be solid or semi-solid at 22° C., but melt into aproper clear solution (and not a suspension) at 37° C. (Table 5).

TABLE 5 Solid Formulations of Pharmaceutical Compositions Compound 600mg Ibuprofen Solvent 500 mg Methanol Adjuvant 2000 mg Palmitic acid 2000mg Stearic acid 250 mg Linolenic acid 250 mg Linoleic acid Ratio 1:9Volume 5 mL Concentration 120 mg/mL

Example 5 Animal Model for Intestinal Erosion

To assess whether a pharmaceutical composition disclosed herein reducedgastric irritation, experiments were conducted using an intestinalerosion murine model.

Sprague-Dawley rats were divided into seven experimental groupscontaining five animals each. After fasting overnight, the animals werechallenged with one with one of seven different treatments. Group A wasa control in which each mouse was orally administered 1%methylcellulose/0.5% polysorbate 80 vehicle only. Group B was a controlin which each mouse was orally administered solvent/adjuvant vehicleonly (gavage of 10% ethanol and 90% linseed oil). Group C was a controlin which each mouse was orally administered 150 mg/kg aspirin. Group Dwas a control in which each mouse was orally administered 100 mg/kgibuprofen suspended in 1% methylcellulose/0.5% polysorbate 80. Group Ewas the experimental group in which each mouse was administered apharmaceutical composition disclosed herein (BC1054-100) comprising 100mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Group F was acontrol in which each mouse was orally administered 100 mg/kg ibuprofensuspended in 1% methylcellulose/0.5% polysorbate 80. Group G was theexperimental group in which each mouse was administered a pharmaceuticalcomposition disclosed herein (BC1054-200) comprising 200 mg/kg ofibuprofen, 10% ethanol, and 90% linseed oil. Animals were sacrificed 4hours after treatment and the stomachs were examined for degree ofhemorrhage and severity of mucosal erosive lesions. Gastric irritationwas scored as follows: 0, no lesions; 1, hyperemia; 2, one or two slightlesions; 3, more than two slight lesions or severe lesions; and 4, verysevere lesions. A score of 50% or more relative to Group C(aspirin-treated control group), which was set to 100%, was considered apositive score for gastric irritation.

Results are shown in Table 6. Group D (100 mg/kg of ibuprofen-treatedcontrol group) and Group F (200 mg/kg of ibuprofen-treated controlgroup) produced gastric lesions that were 75% and 95%, respectively,severe as those induced by Group C (aspirin-treated control group).However, Group E (BC1054-100-treated experimental group) and Group G(BC1054-200-treated experimental group) produced gastric lesions thatwere 20% and 40%, respectively, as severe as those associated with GroupC (aspirin-treated control group). These results demonstrate that that apharmaceutical composition disclosed herein reduced the extent to whicha therapeutic compound may cause mucosal lesions and cause gastricirritation.

TABLE 6 Results from Intestinal Erosion Assay Mean Group UlcerationScore % Aspirin Erosion A 0 0 B 0 0 C 4 (100)  D 3 75¹  E 0.8 20  F 3.895¹  G 1.6 40  ¹Positive score for gastric erosion.

Example 6 Animal Model for a Respiratory Inflammation

To assess the effectiveness of a pharmaceutical composition disclosedherein in treating a respiratory inflammation, experiments wereconducted using a viral-induce influenza murine model.

C57BLK/6 female mice (6-7 weeks old) were divided into threeexperimental groups containing ten animals each. On day 1, animalsreceived an intranasal lethal dose (50 μL total, 25 μL/nostril) ofInfluenza A/PR/8/34 under halothane-induced anaesthesia. On day 3,post-challenge with the virus, the animals received one of threetreatments. Group A was a control in which each mouse was orallyadministered 335.6 μg of ibuprofen dissolved in 10 μL DMSO (noadjuvant). Group B was a control in which each mouse was orallyadministered solvent/adjuvant vehicle only (gavage of 10% ethanol and90% linseed oil). Group C was the experimental group in which each mousewas administered a pharmaceutical composition disclosed herein (BC1054)comprising 335.6 μg of ibuprofen, 10% ethanol, and 90% linseed oil. Adose of 335.6 μg of ibuprofen in the mouse is equivalent to 20mg/kg/day, or 1200 mg/day for a human (the maximum standard dose foribuprofen). Animals were weighed, and monitored for signs of infectiondaily for up to day 6 when all animals were culled. FIG. 1 clearly showsthat oral administration of the solvent/adjuvant vehicle only (Group B)had an 80% mortality rate and that oral administration of ibuprofen only(Group A) exhibited a mortality rate of 60%. However, a single oraladministration of BC1054 reduced the mortality rate to only 20%.

To determination of levels of IL-10 and IL-4, an ELISA was performedusing a 96-well plate coated with a capture antibody for IL-10 or IL-4.Lungs collected from the culled mice were homogenized at 4° C., and thesupernatant collected and stored at −70° C. until needed. Thawed sampleswere vortexed for 30 seconds immediately before adding to the ELISAplate. Serial dilutions were performed within the plate with both thesample and the standards by pipetting 60 μL of assay diluent into eachwell. The plate was sealed and incubated for 2 hours at roomtemperature. For IL-4, 60 μL of working detector was added (DetectionAntibody+SAv-HRP reagent) to each well. The plate was sealed andincubated for 1 hour at room temperature. For IL-10, 60 μL of detectionantibody was diluted in assay diluent to each well. Plates were washedand 60 μL of SAv-HRP enzyme was diluted in assay diluent and added tothe plate. The plate was sealed and incubated for 20 minutes at roomtemperature. Plates were then washed ten times. 60 μL of substratesolution were added to each well and the plate was incubated for 30minutes at room temperature in the dark. 60 μL of stop solution wasadded to each well and absorbance was read at 450 nm. IL-10 and IL-4concentrations were expressed as pg/mg of lung tissue. These resultsindicate that a pharmaceutical composition disclosed herein waseffective in treating a respiratory inflammation.

Results show that animals from the Group A (ibuprofen-treated controlgroup) and Group B (solvent/adjuvant vehicle-treated control group)controls exhibited 2600 pg/mg and 2000 pg/mg of IL-10, respectively(FIG. 2A). However, Group C (BC1054-treated experimental group) revealedan IL-10 concentration of 6000 pg/mg, 3-fold higher than that seen inthe control animals. These result also shows that animals from the GroupA (ibuprofen-treated control group) and Group B (solvent/adjuvantvehicle-treated control group) controls exhibited 6900 pg/mg and 5400pg/mg of IL-4, respectively, while Group C (BC1054-treated experimentalgroup) exhibited an IL-4 concentration of 8300 pg/mg (FIG. 2B). Takentogether, synergistic increase in IL-10 levels and/or the increase inIL-4 levels suggest that at least part of the efficacy observed forBC1054 was by inducing a switch from a Th1 to a Th2 response.

Further experiments were done to further determine which cell types werestimulated to release cytokines upon administration of a BC1054.C57BLK/6 female mice (6-7 weeks old) were divided into threeexperimental groups containing ten animals each. On day 1, animalsreceived an intranasal lethal dose (50 μL total, 25 μL/nostril) ofInfluenza H1N1 under halothane-induced anaesthesia. On day 3,post-challenge with the virus, the animals received one of threetreatments. Group A was a control in which each mouse was orallyadministered 335.6 μg of ibuprofen dissolved in 10 μL DMSO (noadjuvant). Group B was a control in which each mouse was orallyadministered solvent/adjuvant vehicle only (gavage of 10% ethanol and90% linseed oil) (no ibuprofen). Group C was the experimental group inwhich each mouse was administered a pharmaceutical composition disclosedherein (BC1054) comprising 335.6 μg of ibuprofen, 10% ethanol, and 90%linseed oil. Lungs collected from fatally-infected mice were homogenizedat 4° C., and the supernatant collected, stored, and IL-10, TNFα andIFNγ levels measured using an ELISA.

The results show that Group A (ibuprofen-treated control group) andGroup C (BC1054-treated experimental group) animals exhibited anincreased IL-10 levels (FIG. 3A). However, these IL-10 increases wereassociated with very different pharmacodynamic effects, and the patternof pro-inflammatory cytokine reduction highlights the source of theIL-10 and its relevance to the effect on survival. For example, TNFα(which is macrophage-related cytokine) was not as markedly inhibited(FIG. 3B) in Group A (ibuprofen-treated control group) animals, whereasthe levels of IFNγ (which is a lymphocyte-derived cytokine) weremarkedly lowered in this group when compared to Group C (BC1054-treatedexperimental group) animals (FIG. 3C). This cytokine release pattern wasassociated with a poor outcome. However, in Group C (BC1054-treatedexperimental group) animals, TNFα levels were markedly lowered (FIG.3B), while IFNγ levels were largely unaffected (FIG. 3C). Thisdemonstrates that a pharmaceutical composition disclosed herein shows aprotective effect on the H1N1-induced lethality through, in part, amacrophage-derived IL-10 levels rather than lymphocyte-derived IL10.

Example 7 Case Studies for the Treatment of a Cardiovascular Disease

A 49 year old male diagnosed with hypercholesterolemia (LDL of 4.35mmol/L) was placed on a pharmaceutical composition disclosed herein(BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% linseedoil (600 mg bid) for 7 days. After 5 days of treatment the patient's LDLlevels had normalized to 3.89 mmol/L. The normalization of LDL levelpersisted for 2 months after cessation of BC1054 dosing, as determinedat the last examination.

A 60 year old male newly diagnosed with hypercholesterolemia (LDL of4.31 mmol/L) was given a course of a pharmaceutical compositiondisclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol,and 90% linseed oil (1200 mg uid) to lower LDL levels to within thenormal range. After 5 days of treatment the patients LDL levels werelowered to 3.36 mmol/L. The patient was followed up for 1 month and hisLDL remained within the normal range, despite there being no furtherBC1054 dosing.

Example 8 Treatment of Cardiovascular Disease

A 62 year old female is diagnosed with elevated cholesterol levels. Aphysician determines that the elevated cholesterol level is due to ahypercholesterolemia. The woman is treated by oral administration apharmaceutical composition comprising ibuprofen as disclosed hereintaken twice daily. Alternatively, the woman is treated by oraladministration a pharmaceutical composition comprising a PPAR-γ agonistas disclosed herein taken thrice daily. Alternatively, the woman istreated by oral administration a pharmaceutical composition comprisingGemfibrozil as disclosed herein taken twice daily. The woman's conditionis monitored and after about 1 week of treatment tests indicates thereis reduced level of cholesterol in her blood. At one and three monthcheck-ups, the woman continues to have blood cholesterol levels in anormal range. This reduction in a hypercholesterolemia symptom indicatessuccessful treatment with the pharmaceutical composition disclosedherein. A similar type of oral administration of a pharmaceuticalcomposition disclosed herein will be used to treat a patient sufferingfrom other forms of, such as, e.g., dyslipidemia, hypercholesterolemia,hyperglyceridemia, hypertriglyceridemia, hyperchylomicronemia, combinedhyperlipidemia, or hyperlipoproteinemia including hyperlipoproteinemiais hyperlipoproteinemia type Ia, hyperlipoproteinemia type Ib,hyperlipoproteinemia type Ic, hyperlipoproteinemia type IIa,hyperlipoproteinemia type IIb, hyperlipoproteinemia type III,hyperlipoproteinemia type IV, and hyperlipoproteinemia type V. In asimilar manner, any of the therapeutic compounds such as, e.g., a NSAIDlike a salicylate derivative NSAID, a p-amino phenol derivative NSAID, apropionic acid derivative NSAID, an acetic acid derivative NSAID, anenolic acid derivative NSAID, a fenamic acid derivative NSAID, anon-selective cyclo-oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2)inhibitor; a PPARγ agonist; a nuclear receptor binding agent; or ananti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol, aniacin, a bile acid sequestrants, a cholesterol absorption inhibitor, apancreatic lipase inhibitor, or a sympathomimetic amine, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 58 year old male is complains of chest pains, shortness of breath anddizziness. A physician determines that the breathing difficulty is dueto an atherosclerosis. The man is treated by oral administration apharmaceutical composition comprising ibuprofen as disclosed hereintaken twice daily. Alternatively, the man is treated by oraladministration a pharmaceutical composition comprising a PPAR-γ agonistas disclosed herein taken thrice daily. Alternatively, the man istreated by oral administration a pharmaceutical composition comprisingGemfibrozil as disclosed herein taken twice daily. The man's conditionis monitored and after about 3 weeks of treatment the man indicatesthere is improvement in his ability to breath and he is not experiencingas much dizziness. At two and three month check-ups, the man indicatesthat he continues to have improved breathing, no dizziness and no recentchest pains. This reduction in a atherosclerosis symptoms indicatesuccessful treatment with the pharmaceutical composition disclosedherein. A similar type of oral administration of a pharmaceuticalcomposition disclosed herein will be used to treat a patient sufferingfrom another form of vascular occlusive disease such as, e.g., aperipheral vascular disease or a stenosis. In a similar manner, any ofthe therapeutic compounds such as, e.g., a NSAID like a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1)inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor; a PPARγagonist; a nuclear receptor binding agent; or an anti-hyperlipidemicagent like a fibrate, a statin, a tocotrienol, a niacin, a bile acidsequestrants, a cholesterol absorption inhibitor, a pancreatic lipaseinhibitor, or a sympathomimetic amine, will be formulated into apharmaceutical composition and administered to the patient as describedabove.

A 67 year old male suffering from alcoholism complains of pressure onhis chest and numbness in his left shoulder. A physician determines thatthe pressure and numbness are due to an alcoholic cardiomyopathy. Theman is treated by oral administration a pharmaceutical compositioncomprising ibuprofen as disclosed herein taken twice daily.Alternatively, the man is treated by oral administration apharmaceutical composition comprising a PPAR-γ agonist as disclosedherein taken thrice daily. Alternatively, the man is treated by oraladministration a pharmaceutical composition comprising Gemfibrozil asdisclosed herein taken twice daily. The man's condition is monitored andafter about 3 weeks of treatment the man indicates there is reducednumbness. At two and three month check-ups, the man indicates that hecontinues to have improved sensation in his shoulder and has not had arecent episode of chest pressure. This reduction in alcoholiccardiomyopathy symptoms indicates successful treatment with thepharmaceutical composition disclosed herein. A similar type of oraladministration of a pharmaceutical composition disclosed herein will beused to treat a patient suffering from a cardiomyopathy, such as, e.g.,an extrinsic cardiomyopathy like acromegaly, amyloidosis, Chagasdisease, chemotherapy, diabetic cardiomyopathy, hemochromatosis,hypertensive cardiomyopathy, hyperthyroidism, inflammatorycardiomyopathy, ischemic cardiomyopathy, muscular dystrophy, valvularcardiomyopathy, a cardiomyopathy secondary to a systemic metabolicdisease, a cardiomyopathy secondary to a systemic nutritional disease, acoronary artery disease, or a congenital heart disease; or an intrinsiccardiomyopathy like dilated cardiomyopathy (DCM), hypertrophiccardiomyopathy (HCM or HOCM), arrhythmogenic right ventricularcardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), noncompactioncardiomyopathy, isolated ventricular non-compaction, mitochondrialmyopathy, Takotsubo cardiomyopathy, or Loeffler endocarditis. In asimilar manner, any of the therapeutic compounds such as, e.g., a NSAIDlike a salicylate derivative NSAID, a p-amino phenol derivative NSAID, apropionic acid derivative NSAID, an acetic acid derivative NSAID, anenolic acid derivative NSAID, a fenamic acid derivative NSAID, anon-selective cyclo-oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2)inhibitor; a PPARγ agonist; a nuclear receptor binding agent; or ananti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol, aniacin, a bile acid sequestrants, a cholesterol absorption inhibitor, apancreatic lipase inhibitor, or a sympathomimetic amine, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 73 year old female complains of muscle cramping and cold sensationdown her right leg. A physician determines that the symptoms are due toarteritis of the femoral artery. The woman is treated by oraladministration a pharmaceutical composition comprising ibuprofen asdisclosed herein taken twice daily. Alternatively, the woman is treatedby oral administration a pharmaceutical composition comprising a PPAR-γagonist as disclosed herein taken thrice daily. Alternatively, the womanis treated by oral administration a pharmaceutical compositioncomprising Gemfibrozil as disclosed herein taken twice daily. Thewoman's condition is monitored and after about 3 weeks of treatment thewoman indicates that she has reduced muscle cramping and no coldsensations on her leg. At two and three month check-ups, the womanindicates that she still does not have muscle cramping or coldsensations. This reduction in arteritis symptoms indicates successfultreatment with the pharmaceutical composition disclosed herein. Asimilar type of oral administration of a pharmaceutical compositiondisclosed herein will be used to treat a patient suffering from anothertype of vasculitis, such as, e.g., a Buerger's disease, an arteritis, acerebral vasculitis, a Churg-Strauss arteritis, a cryoglobulinemia, anessential cryoglobulinemic vasculitis, a giant cell arteritis, aGolfer's vasculitis, a Henoch-Schonlein purpura, a hypersensitivityvasculitis, a Kawasaki disease, a phlebitis, a microscopicpolyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgiarheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, athrombophlebitis, a Wegener's granulomatosis, a vasculitis secondary toviral infection, or a vasculitis secondary to connective tissue disorderincluding systemic lupus erythematosus (SLE), rheumatoid arthritis (RA),relapsing polychondritis, or Behçet's disease. In a similar manner, anyof the therapeutic compounds such as, e.g., a NSAID like a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1)inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor; a PPARγagonist; a nuclear receptor binding agent; or an anti-hyperlipidemicagent like a fibrate, a statin, a tocotrienol, a niacin, a bile acidsequestrants, a cholesterol absorption inhibitor, a pancreatic lipaseinhibitor, or a sympathomimetic amine, will be formulated into apharmaceutical composition and administered to the patient as describedabove.

A 37 year old male complains of chest pains. A physician determines thatthe pain is due to an endocarditis. The man is treated by oraladministration a pharmaceutical composition comprising ibuprofen asdisclosed herein taken twice daily. Alternatively, the man is treated byoral administration a pharmaceutical composition comprising a PPAR-γagonist as disclosed herein taken thrice daily. Alternatively, the manis treated by oral administration a pharmaceutical compositioncomprising Gemfibrozil as disclosed herein taken twice daily. The man'scondition is monitored and after about 1 week of treatment the manindicates there is reduced chest pain. At one and three month check-ups,the man indicates that he continues to have no chest pain. Thisreduction in a endocarditis symptom indicates successful treatment withthe pharmaceutical composition disclosed herein. A similar type of oraladministration of a pharmaceutical composition disclosed herein will beused to treat a patient suffering from another type of inflammatoryheart disease, such as, e.g., an inflammatory cardiomegaly or amyocarditis. In a similar manner, any of the therapeutic compounds suchas, e.g., a NSAID like a salicylate derivative NSAID, a p-amino phenolderivative NSAID, a propionic acid derivative NSAID, an acetic acidderivative NSAID, an enolic acid derivative NSAID, a fenamic acidderivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, aselective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase2 (COX 2) inhibitor; a PPARγ agonist; a nuclear receptor binding agent;or an anti-hyperlipidemic agent like a fibrate, a statin, a tocotrienol,a niacin, a bile acid sequestrants, a cholesterol absorption inhibitor,a pancreatic lipase inhibitor, or a sympathomimetic amine, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 59 year old female complains about having a shortness of breath and isdiagnosed with high blood pressure. A physician determines that thejoint stiffness and swelling is due to a hypertensive disease. The womanis treated by oral administration a pharmaceutical compositioncomprising ibuprofen as disclosed herein taken twice daily.Alternatively, the woman is treated by oral administration apharmaceutical composition comprising a PPAR-γ agonist as disclosedherein taken thrice daily. Alternatively, the woman is treated by oraladministration a pharmaceutical composition comprising Gemfibrozil asdisclosed herein taken twice daily. The woman's condition is monitoredand after about 3 weeks of treatment the woman indicates that herbreathing is improving and her blood pressure is within the normalrange. At two and three month check-ups, the woman indicates that shecontinues to breathe normally and her blood pressure is within thenormal range. This reduction in a hypertensive symptom indicatessuccessful treatment with the pharmaceutical composition disclosedherein. A similar type of oral administration of a pharmaceuticalcomposition disclosed herein will be used to treat a patient sufferingfrom a cardiovascular disease, such as, e.g., a coronary heart disease,an ischemic heart disease, a congestive heart failure, a hypertensiveheart disease, a valvular heart disease, a hypertension, myocardialinfarction, a diabetic cardiac conditions, an aneurysm; an embolism, adissection, a pseudoaneurysm, a vascular malformation, a vascular nevus,a thrombosis, a varicose vein, or a stroke. In a similar manner, any ofthe therapeutic compounds such as, e.g., a NSAID like a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1)inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor; a PPARγagonist; a nuclear receptor binding agent; or an anti-hyperlipidemicagent like a fibrate, a statin, a tocotrienol, a niacin, a bile acidsequestrants, a cholesterol absorption inhibitor, a pancreatic lipaseinhibitor, or a sympathomimetic amine, will be formulated into apharmaceutical composition and administered to the patient as describedabove.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

The invention claimed is:
 1. A pharmaceutical composition comprising: a) a fibrate; and b) at least 50% of a pharmaceutically-acceptable lipid-adjuvant, wherein the pharmaceutically-acceptable lipid-adjuvant comprises one or more glycerolipids, wherein the pharmaceutical composition is formulated to have a melting point temperature of about 30° C. or higher.
 2. The pharmaceutical composition according to claim 1, wherein the fibrate comprises Bezafibrate, Ciprofibrate, Clofibrate, Fenofibrate, Gemfibrozil, or a combination thereof.
 3. The pharmaceutical composition according to claim 1, wherein the concentration of the fibrate is at least 50 mg/mL.
 4. The pharmaceutical composition according to claim 1, wherein the pharmaceutically-acceptable lipid-adjuvant is in an amount of about 80% to about 97%.
 5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically-acceptable lipid-adjuvant is in an amount of about 80% to about 93%.
 6. The pharmaceutical composition according to claim 5, wherein the pharmaceutically-acceptable lipid-adjuvant is in an amount of about 85% to about 93%.
 7. The pharmaceutical composition according to claim 1, wherein the pharmaceutically-acceptable lipid-adjuvant comprises at least 55% of the pharmaceutically-acceptable lipid-adjuvant.
 8. The pharmaceutical composition according to claim 7, wherein the pharmaceutically-acceptable lipid-adjuvant comprises at least 60% of the pharmaceutically-acceptable lipid-adjuvant.
 9. The pharmaceutical composition according to claim 8, wherein the pharmaceutically-acceptable lipid-adjuvant comprises at least 65% of the pharmaceutically-acceptable lipid-adjuvant.
 10. The pharmaceutical composition according to claim 1, wherein the one or more glycerolipids comprises a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated diglyceride, a triglyceride, an acetylated triglyceride, or any combination thereof.
 11. The pharmaceutical composition according to claim 10, wherein the one or more glycerolipids comprises a monoglyceride, a diglyceride, a triglyceride, or any combination thereof.
 12. The pharmaceutical composition according to claim 11, wherein the pharmaceutically-acceptable lipid-adjuvant comprises at least 40% of a triglyceride, an acetylated triglyceride, or any combination thereof and at least 10% of a monoglyceride, an acetylated monoglyceride, diglyceride or any combination thereof.
 13. The pharmaceutical composition according to claim 11, wherein the pharmaceutically-acceptable lipid-adjuvant comprises at least 45% of a triglyceride, an acetylated triglyceride, or any combination thereof and at least 20% of a monoglyceride, an acetylated monoglyceride, diglyceride or any combination thereof.
 14. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically-acceptable solvent in an amount of about 1% to about 20%.
 15. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically-acceptable polyethylene glycol (PEG) polymer in an amount of about 1% to about 20%.
 16. The pharmaceutical composition according to claim 15, wherein the amount of the pharmaceutically-acceptable PEG polymer is less than 15%.
 17. A method of treating an individual with a cardiovascular disease, the method comprising the step of: administering to the individual in need thereof a pharmaceutical composition according to claim 1, wherein administration results in a reduction in a symptom associated with the cardiovascular disease, thereby treating the individual.
 18. The method according to claim 17, wherein the cardiovascular disease is associated with a hyperlipidemia, a coronary heart disease, an atherosclerosis, a peripheral vascular disease, a cardiomyopathy, a vasculitis, an inflammatory heart disease, an ischemic heart disease, a congestive heart failure, a hypertensive heart disease, a valvular heart disease, a hypertension, myocardial infarction, a diabetic cardiac conditions, an aneurysm; an embolism, a dissection, a pseudoaneurysm, a vascular malformation, a vascular nevus, a thrombosis, a varicose vein, or a stroke.
 19. The method according to claim 17, wherein upon administration to the individual, the pharmaceutical composition comprising the therapeutic compound results in a bio-distribution of the therapeutic compound different than a bio-distribution of the therapeutic compound included in the same pharmaceutical composition, except without the pharmaceutically-acceptable adjuvant.
 20. The method according to claim 17, wherein upon administration to the individual, the pharmaceutical composition reduces gastric or intestinal irritation by at least 5% when compared to the pharmaceutical composition, except without the pharmaceutically-acceptable adjuvant. 